Sulphamoylaryl derivatives and use thereof as medicaments for the treatment of liver fibrosis

ABSTRACT

Potent 5-HT2B antagonist of Formula (A), including stereochemically isomeric forms, and salts, hydrates, solvates thereof and their use wherein R1 to R4 and Ar have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them, alone or in combination with other drugs, in fibrosis and/or cirrhosis prevention or therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase entry under 35 U.S.C. § 371 ofInternational Application No. PCT/CN2018/075362, filed on Feb. 6, 2018,which claims priority to PCT/CN2017/073035, filed Feb. 7, 2017, andPCT/CN2017/080185, filed Apr. 12, 2017.

BACKGROUND ART

Liver fibrosis is a chronic disease in which the damaged parenchymaltissue fails to regenerate. This damage causes liver stellate cells tobe over active and triggers the extra cellular matrix (ECM) synthesis toincrease. Advanced liver fibrosis can result in cirrhosis andlife-threatening live failure. Cirrhosis is a disease of the liver withas a pathological hallmark the development of scar tissue that replacesnormal parenchyma. Damage to these hepatic parenchyma (due toinflammation) leads to activation of the stellate cell, which increasesfibrosis through production of myofibroblasts. This process might resultin the generation of fibrous tissue bands (septa), which eventuallyreplace the entire liver architecture ending in the obstruction of bloodflow.

Recently, it has become clear that 5-HT2B might play a role in theprogression of liver fibrosis and/or cirrhosis. M. Ebrahimkhani et alhave shown that selective antagonism of 5-HT2B enhanced hepatocytegrowth in models of acute and chronic liver injury (Nature Medicine 17,1668-1673 (2011)).

5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotoninreceptor 2B is a protein that in humans is encoded by the HTR2B gene.5-HT2B is a member of the 5-HT2 receptor family that binds theneurotransmitter serotonin (5-hydroxytryptamine, 5-HT).

There is a need for selective and potent 5-HT2B antagonist chemicalclasses, useful in the treatment or prevention of fibrosis and/orcirrhosis.

Amongst the problems which 5-HT2B antagonists may encounter aretoxicity, mutagenicity, lack of selectivity, poor efficacy, poorbioavailability, low solubility and difficulty of synthesis.

There is a need for drugs to treat liver fibrosis and/or cirrhosis, morespecifically 5-HT2B antagonists that may overcome at least one of thesedisadvantages or that have additional advantages such as increasedpotency or an increased safety window.

WO2013/006394, published on Jan. 10, 2013, relates to a subclass ofsulphamoyl-arylamides active against Hepatitis B Virus (HBV).WO2013/096744, published on Jun. 26, 2013 also relates tosulphamoyl-arylamides active against HBV.

DESCRIPTION OF THE INVENTION

Surprisingly it was found that certain sulphamoyl-arylamides are potent5-HT2B antagonist.

The present invention relates to a compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein:

Ar represents a monocyclic or bicyclic aromatic ring, optionallycontaining one or more heteroatoms each independently selected from thegroup consisting of O, S and N, such aromatic ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —CN, —OR⁶, C₁-C₃ alkyl, C₃-C₇cycloalkyl, CHF₂, CH₂F and CF₃;

R¹ represents a 3-7 membered saturated ring optionally containing one ormore heteroatoms each independently selected from the group consistingof O, S and N, such 3-7 membered saturated ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of fluor, —OH, oxo and C₁-C₃ alkyl optionallysubstituted with one or more fluor and/or OH;

R⁶ represents hydrogen, C₁-C₃ alkyl optionally substituted with one ormore fluor, or —C₁-C₃ alkyl-O(R⁵);

R⁵ represents hydrogen or C₁-C₃ alkyl;

or a pharmaceutically acceptable salt or a solvate thereof.

The present invention also relates to use of a compound of Formula (A)

or a stereoisomer or tautomeric form, and/or a salt or solvate thereof,in the manufacture of a medicament for the prevention or treatment offibrosis and/or cirrhosis in a mammal, wherein

Ar represents a monocyclic or bicyclic aromatic ring, optionallycontaining one or more heteroatoms each independently selected from thegroup consisting of O, S and N, such aromatic ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of hydrogen, halogen, —CN, —OH, C₁-C₃ alkyl,C₃-C₇ cycloalkyl, —O(R⁶), CHF₂, CH₂F and CF₃;

R¹ represents hydrogen, a 3-7 membered saturated ring optionallycontaining one or more heteroatoms each independently selected from thegroup consisting of O, S and N, or C₁-C₆ alkyl, such 3-7 memberedsaturated ring or C₁-C₆ alkyl optionally being substituted with one ormore substituents each independently selected from the group consistingof C₁-C₃ alkyl, halogen, CHF₂, CH₂F and CF₃. —CN, —C(═O)R⁵, oxo-C(═O)N(R⁶)₂, —N(R⁶)₂ and —OR⁶;

R² represents hydrogen, or C₁-C₃ alkyl;

R³ represents fluor or —OC₁-C₃ alkyl optionally substituted with one ormore fluor;

R⁴ represents hydrogen, fluor or —OC₁-C₃ alkyl;

R⁶ represents hydrogen, C₁-C₃ alkyl optionally substituted with one ormore fluor, or —C₁-C₃ alkyl-O(R⁵);

R⁵ represents hydrogen or C₁-C₃ alkyl.

The invention further relates to the compound of Formula (I) for use asa medicament, preferably for use in the prevention or treatment offibrosis and/or cirrhosis in a mammal.

The invention also relates to the compound of Formula (A) for use as amedicament, preferably for use in the prevention or treatment offibrosis and/or cirrhosis in a mammal.

The invention further relates to a method for preventing or treatingfibrosis and/or cirrhosis in a mammal, comprising administering thecompound of Formula (I) to the subject in need thereof.

The invention also relates to a method for preventing or treatingfibrosis and/or cirrhosis in a mammal, comprising administering thecompound of Formula (A) to the subject in need thereof.

The invention further relates to use of the compound of Formula (I) inthe manufacture of a medicament for the treatment or the prevention ofliver fibrosis and/or cirrhosis.

The invention further relates to a pharmaceutical composition comprisingcompounds of Formula (I), and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition comprisingcompounds of Formula (I) and Formula (A), and a pharmaceuticallyacceptable carrier.

In a further aspect, the invention relates to a combination of compoundsof Formula (I) and Formula (A), and another fibrosis and/or cirrhosisinhibitor.

The invention also relates to a product containing (a) a compound ofFormula (I), and (b) another fibrosis and/or cirrhosis inhibitor, as acombined preparation for simultaneous, separate or sequential use in thetreatment of fibrosis and/or cirrhosis.

The invention further relates to a product containing (a) compounds ofFormula (I) and Formula (A), and (b) another fibrosis and/or cirrhosisinhibitor, as a combined preparation for simultaneous, separate orsequential use in the treatment of fibrosis and/or cirrhosis.

Definitions

The term “optional” or “optionally” means the event described subsequentthereto may or may not happen. This term encompasses the cases that theevent may or may not happen.

The term “one or more” means one, two, three, four, five, six, seven,eight, nine or more.

The term “aryl” means a monocyclic- or polycyclic aromatic ringcomprising carbon atoms, and hydrogen atoms. If indicated, such aromaticring may include one or more heteroatoms, preferably, 1 to 3heteroatoms, independently selected from nitrogen, oxygen, and sulfur,preferably nitrogen (heteroaryl). As is well known to those skilled inthe art, heteroaryl rings have less aromatic character than theirall-carbon counter parts. Thus, for the purposes of the presentinvention, a heteroaryl group need only have some degree of aromaticcharacter. Illustrative examples of aryl groups are optionallysubstituted phenyl and naphtyl. Illustrative examples of heteroarylgroups according to the invention include optionally substituted,pyridine, pyrimidine, thiazole, indazole.

The terms “C_(1-x) alkyl” and C₁-C_(x) alkyl can be usedinterchangeably.

The term “C₁₋₃ alkyl” as a group or part of a group refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numberranging from 1 to 3. In case C₁₋₃ alkyl is coupled to a further radical,it refers to a Formula C_(n)H_(2n). C₁₋₃ alkyl groups comprise from 1 to3 carbon atoms, more preferably 1 to 2 carbon atoms. C₁₋₃ alkyl includesall linear, or branched alkyl groups with between 1 and 3 carbon atoms,and thus includes such as for example methyl, ethyl, n-propyl, andi-propyl. C₁₋₄ alkyl as a group or part of a group defines straight orbranched chain saturated hydrocarbon radicals having from 1 to 4 carbonatoms such as the group defined for C₁₋₃alkyl and butyl and the like.C₁₋₆ alkyl and C₂₋₆ alkyl as a group or part of a group defines straightor branched chain saturated hydrocarbon radicals having from 1 to 6carbon atoms, or from 2 to 6 carbon atoms such as the groups defined forC₁₋₄alkyl and pentyl, hexyl, 2-methylbutyl and the like.

The term “C₁₋₃ alkyloxy” as a group or part of a group refers to aradical having the Formula —OR^(c) wherein R^(c) is C₁₋₃ alkyl.Non-limiting examples of suitable C₁₋₃ alkyloxy include methyloxy (alsomethoxy), ethyloxy (also ethoxy), propyloxy and isopropyloxy.

The term oxo, C(═O), or carbonyl refers to a group composed of a carbonatom double bonded to an oxygen atom.

As used herein, the term “3-7 membered saturated ring” means saturatedcyclic hydrocarbon (cycloalkyl) with 3, 4, 5, 6 or 7 carbon atoms and isgeneric to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Such saturated ring optionally contains one or more heteroatoms, suchthat at least one carbon atom is replaced by a heteroatom selected fromN, O and S, in particular from N and O. Examples include oxetane,tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl,thiolane 1,1-dioxide and pyrrolidinyl. Preferred are saturated cyclichydrocarbons with 3 or 4 carbon atoms and 1 oxygen atom. Examplesinclude oxetane, and tetrahydrofuranyl.

It should be noted that different isomers of the various heterocyclesmay exist within the definitions as used throughout the specification.For example, pyrrolyl may be 1H-pyrrolyl or 2H-pyrrolyl.

The term halo and halogen are generic to fluoro, chloro, bromo or iodo.Preferred halogens are bromo, fluoro and chloro.

It should also be noted that the radical positions on any molecularmoiety used in the definitions may be anywhere on such moiety as long asit is chemically stable. For instance pyridyl includes 2-pyridyl,3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and3-pentyl.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

When any variable (e.g. halogen or C₁₋₄ alkyl) occurs more than one timein any constituent, each definition is independent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in chemically stable compounds. “Stablecompound” is meant to indicate a compound that is sufficiently robust tosurvive isolation to a useful degree of purity from a reaction mixture,and formulation into a therapeutic agent.

For therapeutic use, the salts of the compounds of Formula (I) are thosewherein the counter ion is pharmaceutically or physiologicallyacceptable. However, salts having a pharmaceutically unacceptablecounter ion may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound of Formula (I).All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

The pharmaceutically acceptable or physiologically tolerable additionsalt forms which the compounds of the present invention are able to formcan conveniently be prepared using the appropriate acids, such as, forexample, inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; hemisulphuric, nitric; phosphoric and thelike acids; or organic acids such as, for example, acetic, aspartic,dodecylsulphuric, heptanoic, hexanoic, nicotinic, propanoic,hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said acid addition salt forms can be converted by treatmentwith an appropriate base into the free base form.

The term “salts” also comprises the hydrates and the solvent additionforms that the compounds of the present invention are able to form.Examples of such forms are e.g. hydrates, alcoholates and the like.

The present compounds may also exist in their tautomeric forms. Forexample, tautomeric forms of amide (—C(═O)—NH—) groups are iminoalcohols(—C(OH)═N—). Tautomeric forms, although not explicitly indicated in thestructural formulae represented herein, are intended to be includedwithin the scope of the present invention.

The term stereochemically isomeric forms of compounds of the presentinvention, as used hereinbefore, defines all possible compounds made upof the same atoms bonded by the same sequence of bonds but havingdifferent three-dimensional structures which are not interchangeable,which the compounds of the present invention may possess. Unlessotherwise mentioned or indicated, the chemical designation of a compoundencompasses the mixture of all possible stereochemically isomeric formswhich said compound may possess. Said mixture may contain alldiastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the compounds ofthe present invention both in pure form or in admixture with each otherare intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates asmentioned herein are defined as isomers substantially free of otherenantiomeric or diastereomeric forms of the same basic molecularstructure of said compounds or intermediates. In particular, the term‘stereoisomerically pure’ concerns compounds or intermediates having astereoisomeric excess of at least 80% (i.e. minimum 90% of one isomerand maximum 10% of the other possible isomers) up to a stereoisomericexcess of 100% (i.e. 100% of one isomer and none of the other), more inparticular, compounds or intermediates having a stereoisomeric excess of90% up to 100%, even more in particular having a stereoisomeric excessof 94% up to 100% and most in particular having a stereoisomeric excessof 97% up to 100%. The terms ‘enantiomerically pure’ and‘diastereomerically pure’ should be understood in a similar way, butthen having regard to the enantiomeric excess, respectively thediastereomeric excess of the mixture in question.

Pure stereoisomeric forms of the compounds and intermediates of thisinvention may be obtained by the application of art-known procedures.For instance, enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or bases. Examples thereof are tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid.Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occurs stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The stereometric forms of Formula (I) can be obtained separately byconventional methods. Appropriate physical separation methods that mayadvantageously be employed are, for example, selective crystallizationand chromatography, e.g. column chromatography.

The present invention is also intended to include all isotopes of atomsoccurring on the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of Hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

DETAILED DESCRIPTION OF THE INVENTION

Whenever used hereinafter, the term “the compounds of the presentinvention” or “the present compounds” or similar term is meant toinclude all compounds of general Formula (I) and Formula (A), andcompounds listed in table 1, salts, stereoisomeric forms and racemicmixtures and any subgroups thereof.

In a first aspect, the present invention provides compounds of Formula(I)

or a stereoisomer or tautomeric form thereof, wherein:

Ar represents a monocyclic or bicyclic aromatic ring, optionallycontaining one or more heteroatoms each independently selected from thegroup consisting of O, S and N, such aromatic ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —CN, —OR⁶, C₁-C₃ alkyl,C₃-C₇cycloalkyl, CHF₂, CH₂F and CF₃;

R¹ represents a 3-7 membered saturated ring optionally containing one ormore heteroatoms each independently selected from the group consistingof O, S and N, such 3-7 membered saturated ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of fluor, —OH, oxo and C₁-C₃ alkyl optionallysubstituted with one or more fluor and/or OH;

R⁶ represents hydrogen, C₁-C₃ alkyl optionally substituted with one ormore fluor, or —C₁-C₃ alkyl-O(R⁵);

R⁵ represents hydrogen or C₁-C₃ alkyl:

or a pharmaceutically acceptable salt or a solvate thereof.

In one embodiment of the present invention, Ar is phenyl, pyridine orbenzimidazole optionally substituted with one or more substituents eachindependently selected from the group consisting of —CN, halogen, C₁-C₃alkyl, C₁-C₃cycloalkyl, CHF₂, CH₂F and CF₃.

In yet another embodiment, Ar is phenyl or pyridine, optionallysubstituted with one or more substituents each independently selectedfrom halogen, —OH, C₁-C₃ alkyl, C₁-C₃cycloalkyl, CHF₂, CH₂F and CF₃.

In a further embodiment, R¹ represents a 4-7 membered saturated ringcontaining carbon atoms and optionally one oxygen atom, such 4-7membered saturated ring optionally substituted with one or more C₁-C₃alkyl and/or OH.

In another embodiment, R¹ represents a 5 membered saturated ringcontaining carbon atoms and one oxygen atom, optionally substituted withone or more C₁-C₃ alkyl and/or OH. In a preferred embodiment, R¹represents a 5 membered saturated ring containing carbon atoms and oneoxygen atom.

In another aspect, the present invention provides use of compounds ofFormula (A)

or a stereoisomer or tautomeric form, and/or a salt or solvate thereof,in the manufacture of a medicament for the prevention or treatment offibrosis and/or cirrhosis in a mammal,

wherein

Ar represents a monocyclic or bicyclic aromatic ring, optionallycontaining one or more heteroatoms each independently selected from thegroup consisting of O, S and N, such aromatic ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of hydrogen, halogen, —CN, —OH, C₁-C₃ alkyl,C₃-C₇cycloalkyl, —O(R⁶), CHF₂, CH₂F and CF₃;

R¹ represents hydrogen, a 3-7 membered saturated ring optionallycontaining one or more heteroatoms each independently selected from thegroup consisting of O, S and N, or C₁-C₆ alkyl, such 3-7 memberedsaturated ring or C₁-C₆ alkyl optionally being substituted with one ormore substituents each independently selected from the group consistingof C₁-C₃ alkyl, halogen, CHF₂, CH₂F and CF₃, —CN, —C(═O)R⁵, oxo, —C(═O)N(R⁶)₂, —N(R⁶)₂ and —OR⁶;

R² represents hydrogen, or C₁-C₃ alkyl;

R³ represents fluor or —OC₁-C₃ alkyl optionally substituted with one ormore fluor;

R⁴ represents hydrogen, fluor or —OC₁-C₃ alkyl;

R⁶ represents hydrogen, C₁-C₃ alkyl optionally substituted with one ormore fluor, or —C₁-C₃ alkyl-O(R⁵);

R⁵ represents hydrogen or C₁-C₃ alkyl.

In one embodiment of the present invention, R³ represents fluor or—OC₁-C₃ alkyl and R² and R⁴ represent hydrogen.

In a further embodiment, Ar is phenyl, pyridine or benzimidazoleoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, C₁-C₃ alkyl,C₁-C₃cycloalkyl, CHF₂, CH₂F and CF₃.

In another embodiment, R¹ represents a 5 membered saturated ringcontaining carbon atoms and one oxygen atom, optionally substituted withone or more C₁-C₃ alkyl and/or OH. In a preferred embodiment, R¹represents a 5 membered saturated ring containing carbon atoms and oneoxygen atom.

In yet another embodiment, Ar is phenyl optionally substituted with oneor more substituents each independently selected from —CN, C₁-C₃ alkyl,C₁-C₃cycloalkyl, CHF₂, CH₂F and CF₃.

Further combinations of any of the embodiments as described for bothFormula (I) and Formula (A) are also envisioned to be in the scope ofthe present invention.

Preferred compounds according to the invention are compound or astereoisomer or tautomeric form thereof with a Formula as represented inthe synthesis of compounds section and of which the activity isdisplayed in Table 1.

In a further aspect, the present invention concerns a pharmaceuticalcomposition comprising a therapeutically or prophylactically effectiveamount of a compound of Formula (I) or Formula (A) as specified herein,and a pharmaceutically acceptable carrier. In still a further aspect,this invention relates to a process of preparing a pharmaceuticalcomposition as specified herein, which comprises intimately mixing apharmaceutically acceptable carrier with a therapeutically orprophylactically effective amount of a compound of Formula (I), asspecified herein.

Therefore, the compounds of the present invention or any subgroupthereof may be formulated into various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically administering drugs.To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areemployed. For parenteral compositions, the carrier will usually comprisesterile water, at least in large part, though other ingredients, forexample, to aid solubility, may be included. Injectable solutions, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Also includedare solid form preparations intended to be converted, shortly beforeuse, to liquid form preparations. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not introduce a significant deleterious effect on theskin. The compounds of the present invention may also be administeredvia oral inhalation or insufflation in the form of a solution, asuspension or a dry powder using any art-known delivery system.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills,suppositories, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

The compounds of Formula (I) are potent 5-HT2B antagonist.

The compounds of the present invention are potent antagonists of5-Hydroxytryptamine receptor 2B (5-HT2B). Due to their 5-HT2B antagonistproperties, the compounds of Formula (I) and Formula (A) or any subgroupthereof, are useful in the inhibition of 5-HT2B enhanced hepatocytegrowth, in particular in the treatment of liver fibrosis and/orcirrhosis in warm-blooded animals, in particular humans, and for theprophylaxis of liver fibrosis and/or cirrhosis. The present inventionfurthermore relates to a method of treating liver fibrosis and/orcirrhosis in a warm-blooded animal, in particular human, or being atrisk of infection by HBV, said method comprising the administration of atherapeutically effective amount of compounds of Formula (I) and Formula(A).

The compounds of Formula (I) and Formula (A), as specified herein, maytherefore be used as a medicine, in particular as medicine to treat orprevent liver fibrosis and/or cirrhosis. Said use as a medicine ormethod of treatment comprises the systemic administration to subjectswith liver fibrosis and/or cirrhosis or to subjects susceptible to liverfibrosis and/or cirrhosis of an amount effective to combat theconditions associated with liver fibrosis and/or cirrhosis or an amounteffective to prevent liver fibrosis and/or cirrhosis.

The present invention also relates to use of the present compounds inthe manufacture of a medicament for the treatment or the prevention ofliver fibrosis and/or cirrhosis.

In general it is contemplated that an anti-fibrosis and/or cirrhosiseffective daily amount would be from about 10 to about 200 mg/kg. It maybe appropriate to administer the required dose as two, three, four ormore sub-doses at appropriate intervals throughout the day. Saidsub-doses may be formulated as unit dosage forms, for example,containing about 1 to about 500 mg, or about 1 to about 300 mg, or about1 to about 100 mg, or about 2 to about 50 mg of active ingredient perunit dosage form.

The present invention also concerns combinations of compounds of Formula(I) and Formula (A) or any subgroup thereof, as specified herein withother agents for treating liver fibrosis and/or cirrhosis. The term“combination” may relate to a product or kit containing (a) compounds ofFormula (I) and Formula (A), as specified above, and (b) at least oneother compound capable of treating liver fibrosis and/or cirrhosis, as acombined preparation for simultaneous, separate or sequential use intreatment of liver fibrosis and/or cirrhosis. In an embodiment, theinvention concerns combination of compounds of Formula (I) and Formula(A) or any subgroup thereof with at least one other agent for treatingliver fibrosis and/or cirrhosis. In a particular embodiment, theinvention concerns combination of compounds of Formula (I) and Formula(A) or any subgroup thereof with at least two other agents for treatingliver fibrosis and/or cirrhosis. In a particular embodiment, theinvention concerns combination of compounds of Formula (I) and Formula(A) or any subgroup thereof with at least three other agents fortreating liver fibrosis and/or cirrhosis. In a particular embodiment,the invention concerns combination of compounds of Formula (I) andFormula (A) or any subgroup thereof with at least four agents fortreating liver fibrosis and/or cirrhosis.

The term agent for treating liver fibrosis and/or cirrhosis alsoincludes compounds that are therapeutic nucleic acids, antibodies orproteins either in their natural form or chemically modified and orstabilized. The term therapeutic nucleic acid includes but is notlimited to nucleotides and nucleosides, oligonucleotides polynucleotidesof which non limiting examples are antisense oligonucleotides, miRNA,siRNA, shRNA, therapeutic vectors and DNA/RNA editing components.

The combination of previously known agents for treating liver fibrosisand/or cirrhosis, and compounds of Formula (I) and Formula (A) or anysubgroup thereof can be used as a medicine in a combination therapy.

Generic Synthesis:

The substituents (R1 and Ar) represented in this general synthesissection are meant to include any substituent or reactive aromatic aminewhich is suitable for transformation into any substituent according tothe present invention without undue burden for the person skilled in theart.

The general synthesis of compound of Formula (IV) is described in scheme1 and scheme 2 in four different methods (method A-D). As described inscheme 1, an 2-methoxybenzoic acid of general Formula (I) is reactedwith sulfurochloridic acid to form a chlorosulfonyl methoxybenzoic acidof general formula (II), which was followed by benzoyl chlorideformation and reacts with aromatic amine to transform a amide of generalFormula (III). The final product was synthesized reacting with an amineto provide sulfonyl amide with general formula (IV). The detailedsynthetic procedure was shown with an example of synthesis of compound1.

Method A (Compound 1 as Example) Intermediate 1.2:5-(Chlorosulfonyl)-2-methoxybenzoic acid

2-Methoxybenzoic acid (30.0 g, 197 mmol) was dissolved in chlorosulfonicacid (115 g, 986 mmol) at 0° C. The resultant reaction mixture washeated at 50° C. for 1 hour. After cooling to room temperature, themixture was poured into ice water and precipitation formed. Theprecipitation was collected and dried to give the title compound (6.00g, 25% yield).

¹H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=2.2 Hz, 1H), 7.67 (dd, J=2.3, 8.7Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 3.79 (s, 3H).

Intermediate 1.3:3-((4-Fluoro-3-methylphenyl)carbamoyl)-4-methoxybenzene-1-sulfonylchloride

5-(Chlorosulfonyl)-2-methoxybenzoic acid (6.00 g, 22.7 mmol, purity 95%)was dissolved in a mixture of DMF (0.5 mL) and DCM (60 mL) followed bythe addition of oxalyl dichloride (14.4 g, 114 mmol) at 0° C. Themixture was stirred at 20° C. for 12 hours before concentrating it todryness. The residue was dissolved in anhydrous toluene (100 mL) andthen 4-fluoro-3-methylaniline (2.79 g, 22.3 mmol) were added. Thereaction was heated to reflux for 1 h and concentrated under reducedpressure. The residue was purified by column chromatography over silicagel (petroleum ether:ethyl acetate=1:1) to give the crude product whichwas recrystallized from ethyl acetate (20 mL) to give the title compound(4.50 g, 55% yield, purity 98%).

LCMS (ESI): R_(T)=0.81 min, mass calcd. for C₁₅H₁₃ClFNO₄S 357.02, m/zfound 357.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 7.83 (d,J=2.0 Hz, 1H), 7.69 (dd, J=2.4, 8.7 Hz, 1H), 7.65 (dd, J=2.5, 7.0 Hz,1H), 7.58-7.52 (m, 1H), 7.14-7.06 (m, 2H), 3.89 (s, 3H), 2.23 (d, J=1.8Hz, 3H).

Compound 1:5-(N-(3,3-Difluorocyclobutyl)sulfamoyl)-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

3-((4-Fluoro-3-methylphenyl)carbamoyl)-4-methoxybenzene-1-sulfonylchloride (200 mg, 0.559 mmol) was dissolved in DCM (10 mL) followed bythe addition of 3,3-difluorocyclobutanamine (65.9 mg, 0.615 mmol) andtriethylamine (170 mg, 1.68 mmol) at 0° C. The mixture was stirred for 1h at 20° C. and then concentrated to dryness under reduce pressure. Theresidue was purified by prep. HPLC (column: Agela DuraShell C18 150mm×25 mm, 5 μm; mobile phase: CH₃CN in water (0.05% base water) from 43%to 73%, flow rate: 30 mL/min). The pure fractions were collected and thevolatiles were removed under vacuum. The residue was suspended in water(5 mL). The aqueous layer was lyophilized to dryness to give the titlecompound as a white solid (67.9 mg, 28% yield, and purity 97.7%).

LC-MS (ESI): R_(T)=5.17 min, mass calcd. for C₁₉H₁₉F₃N₂O₄S 428.10, m/zfound 429.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (br.s., 1H), 8.14(br. s., 1H), 7.97 (d, J=2.4 Hz, 1H), 7.91 (dd, J=2.4, 8.8 Hz, 1H),7.65-7.60 (m, 1H), 7.58-7.52 (m, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.13 (t,J=9.2 Hz, 1H), 3.97 (s, 3H), 3.61-3.49 (m, 1H), 2.78-2.68 (m, 2H),2.43-2.33 (m, 2H), 2.24 (s, 3H).

The other three possible routes to compound of general Formula (IV) aredescribed in scheme 2. The chlorosulfonylmethoxybenzoate was reactedwith amine to give sulfonyl amide of general Formula (V). This sulfonylamide benzoate was used as a reagent for the final product formation orconverted to the other reagents benzoic acid and benzoic chloride byhydrolysis and chloride formation in sequence. The final compounds ofgeneral Formula (IV) were formed through method B, C and D by an amideformation with reagent V, VI, VII respectively. The detailed syntheticprocedure was shown with an example of synthesis of compound 2, 3, 4.

Method B (Compound 2 as Example) Intermediate 2.2: (S)-Methyl2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate

To a solution consisting of (S)-3-aminotetrahydrofuran hydrochloride(3.74 g, 30.2 mmol, Shanghai Nuohey Chemical Technology CO., LTD.), TEA(12.6 mL, 90.7 mmol) and DCM (100 mL) was added methyl5-(chlorosulfonyl)-2-methoxybenzoate (8.00 g, 30.2 mmol). The mixturewas stirred at room temperature for 2 hours and the resultant solutionwas concentrated under reduced pressure. Water and ethyl acetate wereadded. The organic layer was separated and the water phase was extractedtwice with ethyl acetate. The combined organic layers were washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure to give the title compound (7.50 g, 71% yield).

Compound 2:(S)—N-(5-fluoro-6-methylpyridin-2-yl-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LHMDS (2.84 mL, 2.84 mmol, 1 M in THF) was added into a solutionconsisting of(S)-methyl2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate (150 mg, 0.476mmol), oxazol-2-amine (85.7 mg, 0.680 mmol) and THF (5 mL) at 0° C.under nitrogen. The reaction mixture was stirred at 0° C. for 1 hour.The mixture was quenched with saturated NH₄Cl and the resulting mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure to give a residue which was purified by prep.TLCto give title compound (61.9 mg, 22.27% yield, purity 99.1%). LC-MS(ESI): mass calcd. for C₁₈H₂₀FN₃O₅S 409.4, m/z found 410.1 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.60 (br.s, 1H), 8.15-8.02 (m, 2H), 7.96-7.86(m, 2H), 7.69 (t, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 3.99 (s, 3H),3.72-3.61 (m, 2H), 3.60-3.51 (m, 2H), 3.44-3.39 (m, 1H), 2.44-2.30 (m,3H), 1.93-1.81 (m, 1H), 1.65-1.54 (m, 1H).

Method C: (Compound 3 as Example) Intermediate 3.2:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfanoyl)benzoic acid

Lithium hydroxide (3.99 g, 95.1 mmol) was added into a solutionconsisting of (S)-methyl2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate (15 g, 47.6mmol) in THF (100 mL) and H₂O (25 mL). The reaction mixture was stirredat room temperature for 2 hour before concentrating it under reducedpressure to remove volatiles. The resultant aqueous phase was adjust topH=3 with aq. HCl solution and the precipitation was collected and driedto give (S)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoic acid(11.0 g, 69% yield).

Intermediate 3.3:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamyl)benzoyl chloride

Oxalyl dichloride (8.99 mL, 106 mmol) was added into a solutionconsisting of(S)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoicacid (8.00 g, 26.6 mmol), DMF (0.5 mL) and DCM (80 mL) at 0° C. Thereaction was stirred at room temperature for 2 hours. The resultantmixture was concentrated under reduced pressure to give the titlecompound (8.49 g, 90% yield) which was used for the next step directly.

Compound 3:(S)—N-(2-Chloro-3-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoyl chloride (200mg, 0.625 mmol) was dissolved in dry DCM (2 mL) and the resultantsolution was added drop-wise to a well stirred solution consisting of2-chloro-3-fluoroaniline (109 mg, 0.749 mmol), TEA (0.3 mL) and DCM (2mL) at room temperature. The reaction mixture was stirred at roomtemperature for 1 hour and then diluted with DCM (15 mL). Water (10 mL)was added. The organic phase was separated, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to give aresidue which was purified by trituration in DCM (2˜3 mL). The solid wasfiltered and then dried in vacuum. The resultant product was purified byprep. SFC separation (Column: ChiralPak AD 250×30 mm I.D., 10 μm, DaicelChemical Industries, Ltd; Mobile phase: A: Supercritical CO₂, B: EtOH(0.1% NH₃.H₂O), A:B=55:45 at 80 mL/min; Column Temp: 38° C.; NozzlePressure: 100 Bar; Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; TrimmerTemp: 25° C.; Wavelength: 220 nm). The pure fractions were collected andthe volatiles were removed under vacuum. The residue was partitionedbetween CH₃CN (1 ml) and water (5 ml). The solution was lyophilized togive title compound.

LC-MS (ESI): R_(T)=4.93 min, mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/zfound 429.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (br.s, 1H),8.48-8.38 (m, 1H), 8.25-8.15 (m, 1H), 8.05-7.95 (m, 2H), 7.56-7.40 (m,2H), 7.25 (t, J=8.8 Hz, 1H), 4.15 (s, 3H), 3.75-3.50 (m, 4H), 3.40-3.30(m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Method D: (Compound 4 as Example) Compound 4:(S)—N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

HATU (608.4 mg, 1.60 mmol) was added into a mixture consisting of(S)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoic acid (400.1mg, 1.33 mmol), 4-fluoro-3-methylaniline (166.4 mg, 1.33 mmol), TEA(0.56 mL, 4.02 mmol) and DMF (5 mL). The reaction mixture was stirred atroom temperature for 12 hours before pouring it into water. The aqueouslayer was extracted three times with ethyl acetate (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated to dryness to give a residuewhich was purified by prep.HPLC (Column: Gemini 150×25 mm×5 um, Flowrate: 30 ml/min, Mobile Phase A: Base water (containing 0.05% NH3.H2O),Mobile Phase B: Acetonitrile) to give the title compound (100.7 mg,yield 18.1%).

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (br.s, 1H), 8.00 (d, J=2.3 Hz,1H), 7.96-7.876 (m, 2H), 7.63 (dd, J=7.0 Hz, J=2.3 Hz 1H), 7.58-7.53 (m,1H), 7.38 (d, J=9.0 Hz, 1H), 7.13 (t, J=9.1 Hz, 1H), 3.97 (s, 3H),3.74-3.65 (m, 2H), 3.64-3.55 (m, 2H), 3.38-3.35 (m, 1H), 2.24 (s, 3H),1.96-1.85 (m, 1H), 1.67-1.57 (m, 1H).

General Procedure LCMS Analytical Methods

M 1: reverse phase LC-MS was carried out on a YMC-PACK ODS-AQ, 50×2.0 mm5 μm column with a flow rate of 0.8 mL/min, eluting with a gradient of0% to 60% acetonitrile containing 0.05% TFA (solvent B) and watercontaining 0.1% TFA (solvent A). The eluent composition was kept at 100%A for 1 minute, followed by increasing to 60% B over the course of 4minutes. The eluent was kept at 60% B for 2.5 minutes before returningto 100% A over the course of 0.5 minutes. Total run time was 8 minutes.

M2: reverse phase LC-MS was carried out on a Agilent TC-C18, 50×2.1 mm,5 μm column with a flow rate of 0.8 mL/min, eluting with a gradient of0% to 85% acetonitrile containing 0.05% TFA (solvent B) and watercontaining 0.1% TFA (solvent A). The eluent composition was kept at 100%A for 1 minute, followed by increasing to 40% B over the course of 4minutes. The eluent was further increased to 85% B over the course of2.5 minutes before returning to 100% A over the course of 2 minutes.Total run time was 9.5 minutes.

M3: reverse phase LC-MS was carried out on a Agilent TC-C18, 50×2.1 mm,5 μm column with a flow rate of 0.8 mL/min, eluting with a gradient of10% to 80% acetonitrile containing 0.05% TFA (solvent B) and watercontaining 0.1% TFA (solvent A). The eluent composition was kept at 10%B for 0.8 minutes, followed by increasing to 80% B over the course of3.7 minutes. The eluent was kept at 80% B for 3 minutes before returningto 10% B over the course of 2 minutes. Total run time was 9.5 minutes.

M4: reverse phase LC-MS was carried out on a X-Bridge Shield RP18,50×2.1 mm 5 μm with a flow rate of 0.8 mL/min, eluting with a gradientof 0% to 95% acetonitrile (solvent B) and water with 0.05% NH₃.H₂O(solvent A). The eluent composition was kept at 100% A for 1 minute,followed by increasing to 60% B over the course of 4 minutes. The eluentwas increased to 95% B over the course of 2 minutes before returning to100%/o A over the course of 2 minutes. Total run time was 9.5 minutes.

General Methods of Preparation HPLC:

NH₃H₂O: (Column: Agela DuraShell C18 150 mm×25 mm, 5 μm; mobile phase:CH₃CN in water (0.05% NH₃H₂O water) from 43% to 73%, flow rate: 30mL/min).

NH₄HCO₃: (Column: Agela DuraShell C18 150 mm×25 mm, 5 μm; mobile phase:CH₃CN in water (0.5% NH₄HCO₃ water) from 20% to 60%, flow rate: 30mL/min).

Formic acid: (Column: Phenomenex Synergi Max-RP 250 mm×80 mm, 10 μm;mobile phase: CH₃CN in water (0.225% formic acid water) from 1% to 25%,flow rate: 80 ml/min)

HCl: (Column: Gemini C18 150 mm×25 mm, 5 μm; mobile phase: CH₃CN inwater (0.05% HCl water) from 35% to 65%, flow rate: 25 mL/min).

TFA: (Column: Phenomenex Synergi C18 150 mm×30 mm, 4 μm (eluent:CH₃CN/H₂O (0.1% TFA water) from 65% to 75%, flow rate: 30 ml/min).

General SFC Separation Methods:

Method 1: Separation condition: Column: AD 250×30 mm I.D., 5 um, DaicelChemical Industries, Ltd; Mobile phase: A: Supercritical CO₂, B: MeOH(0.1% NH₃H₂O)

Method 2: Separation condition: Column: ChiralPak OJ-H 250×30 mm I.D., 5um, Daicel Chemical Industries, Ltd; Mobile phase: A: Supercritical CO₂,B: EtOH (0.1% NH₃H₂O)

Method 3: Separation condition: Column: ChiralPak AD 250×30 mm I.D., 20um, Daicel Chemical Industries, Ltd; Mobile phase: A: Supercritical CO₂,B: EtOH (0.1% NH₃H₂O)

Method 4: Separation condition: Column: ChiralPak AD, Daicel ChemicalIndustries, Ltd, 250×30 mm I.D., 10 μm; Mobile phase: A: SupercriticalCO₂, B: methanol (0.1% NH₃H₂O)

Method 5: Separation condition: Column: AD (250 mm*30 mm, 5 um); Mobilephase: A: Supercritical CO₂, B: EtOH (0.1% NH₃H₂O);

Method 6: Separation condition: Column: ChiralPak AD 250×30 mm I.D., 10μm, Daicel Chemical Industries, Ltd; Mobile phase: A: Supercritical CO₂,B: EtOH (0.1% NH₃H₂O)

Method 7: Column: Chiralpak AD-3 50*4.6 mm I.D., 3 um Mobile phase: 60%ethanol (0.05% DEA) in CO₂.

Method 8: separation condition: Column: ChiralPak OJ-H, Daicel ChemicalIndustries, Ltd, 250×30 mm I.D., 5 μm; Mobile phase: A: SupercriticalCO₂, B: Methanol (0.1% NH₃H₂O)

TABLE 1 Synthetic Prep. Prep. Analytic # Structure Method HPLC SFC LC-MS 1

A NH₃H₂O / M2  2

B / / M2  3

C / / M2  4

D NH₃H₂O / M2  5

A TFA / M2    6a

A NH₃H₂O Method 1 M2   6b

A NH₃H₂O Method 1 M2  7

A / / M3    7a

A / Method 1 M3   7b

A / Method 1 M3  8

A / / M3  9

A / / M2  10

A / / M2    10a

A / / M2  10b

A / / M2    11a

A / Method 2 M2  11b

A / Method 2 M2  12

A / / M2    12a

A / / M2  12b

A NH₄HCO₃ / M2  13

A / / M2  14

A / / M3    15a

A NH₃H₂O Method 3 M4  15b

A / Method 3 M2    16a

A NH₃H₂O Method 4 M2  16b

A NH₃H₂O Method 4 M2  17

A / / M2  18

A / / M2  19

A / / M2  20

A NH₃H₂O / M2  21

A NH₃H₂O / M3  22

A NH₃H₂O / M4    23a

A NH₃H₂O Method 4 M2  23b

A NH₃H₂O Method 4 M2  24

A NH₃H₂O / M2  25

A NH₃H₂O / M4  26

A NH₃H₂O / M2  27

A NH₃H₂O / M2    28a

A NH₃H₂O Method 4 M2  28b

A NH₃H₂O Method 4 M2    29a

A / Method 1 M2  29b

A / Method 1 M2  30

A / / M2  31

A / Method 4 M2    32a

A Formic acid Method 5 M2  32b

A Formic acid Method 5 M2    33a

A Formic acid Method 4 M2  33b

A Formic acid Method 4 M2    34a

A / / M2  34b

A / / M4    35a

A / / M2  35b

A / / M4  36

A HCl / M2  37

A HCl / M2  38

A HCl / M2  39

A HCl / M2    40a

A / Method 5 M2  40b

A / Method 5 M2  41

A NH₄HCO₃ / M2  42

A NH₄HCO₃ / M2  43

A NH₄HCO₃ / M2    44a

A NH₄HCO₃ Method 5 M2  44b

A NH₄HCO₃ Method 5 M2    45a

A / Method 1 M2  45b

A / Method 1 M2    46a

A / / M2  46b

A HCl / M2  47

A HCl / M2  48

A / / M2    49a

A / / M2  49b

A / / M2  50

A / / M2  51

A / / M2    52a

A / Method 6 M2  52b

A / Method 6 M2  53

A / / M2    54a

A / Method 1 M2  54b

A / Method 1 M2    55a

A / / M2  55b

A / / M2    56a

A NH₃H₂O Method 5 M2  56b

A NH₃H₂O Method 5 M2    57a

A / Method 6 M2  57b

A / Method 6 M2  58

A / / M2    59a

A / / M2  59b

A / / M2    60a

A / Method 5 M2  60b

A / Method 5 M4    61a

A NH₃H₂O / M2  61b

A NH₃H₂O Method 7 M4    61c

A NH₃H₂O Method 7 M4  62

A NH₃H₂O / M2  63

B / / M2  64

C NH₃H₂O / M2  65

C / / M2  66

B / / M2  67

C / / M2  68

C / / M2  69

C / / M2  70

C / / M2  71

C / / M2  72

C / / M2  73

C / / M2  74

C / / M2  75

C / / M2  76

C / / M2  77

C / / M2  78

C / / M2  79

C / / M2  80

C / / M2  81

C NH₃H₂O / M2  82

B / / M2  83

B / / M2  84

B / / M2  85

C / / M2  86

C / / M3  87

C / / M2  88

C / / M2  89

C / / M2  90

C / / M2  91

C NH₃H₂O / M2  92

C / / M2  93

C / / M2  94

C / / M2  95

C / / M2  96

C / / M2  97

C / / M2  98

C / / M2  99

B / / M2 100

B / / M2 101

B / / M1 102

B / / M1 103

B / / M2 104

B / / M1 105

B / / M4 106

B / / M2 107

B / / M2 108

B / / M2 109

B / / M2 110

B / / M2 111

B / / M2 112

B / / M2 113

B / / M2 114

B / / M2 115

B / / M2 116

B / / M2 117

B / / M2 118

B HCl / M2 119

B / / M2 120

B / / M2 121

B / / M2 122

B HCl / M2 123

B / / M2 124

B / / M2 125

B / / M2 126

B / / M2 127

C / / M2 128

B / / M2 129

B / / M2 130

B NH₃H₂O / M2 131

B / / M2 132

B NH₃H₂O / M4 133

B NH₃H₂O / M2 134

B NH₃H₂O / M2 135

B NH₃H₂O / M2 136

B NH₃H₂O / M2   137a

B HCl / M4  137b

B HCl / M4   138a

B HCl Method 6 M2  138b

B HCl Method 6 M2   139a

B HCl Method 6 M2  139b

B HCl Method 6 M2   140a

B HCl Method 6 M2  140b

B HCl Method 6 M4 141

A NH₃H₂O / M2)   142a

B HCl Method 6 M2  142b

B HCl Method 6 M2   143a

B HCl Method 6 M2  143b

B HCl Method 6 M2   144a

B HCl Method 6 M2  144b

B HCl Method 6 M2   145a

B HCl Method 6 M2  145b

B HCl Method 6 M2   146a

B HCl Method 6 M2  146b

B HCl Method 6 M2   147a

B / / M2  147b

B / / M2 148

A NH₃H₂O / M4 149

B / / M2 150

B / / M2 151

C / / M2 152

B NH₃H₂O / M2 153

B NH₃H₂O / M2 154

C NH₄HCO₃ Method 8 M2 155

C NH₄HCO₃ Method 8 M2 156

B NH₄HCO₃ / M2 157

B NH₄HCO₃ / M2 158

D NH₃H₂O / M2 159

D NH₃H₂O / M2 160

D / / M4 161

D / / M2 162

C NH₃H₂O / M1 163

B / / M2 164

B / / M4 165

B / / M4 166

B / / M2 167

D / / M2 168

/ / / M2 169

/ / / M4 170

/ NH₄HCO₃ / M2 171

/ / / M4 172

/ / / M4 173

/ HCl / M2   174a

/ NH₃H₂O Method 6 M4  174b

/ NH₃H₂O Method 6 M2 175

/ / / M2 176

/ TFA / M2 177

/ / / M2 178

/ NH₄HCO₃ / M2 179

/ / / M2 180

/ / / M2 181

/ / / M4 182

/ NH₃H₂O / M4 183

/ / / M2 184

/ / / M4 185

/ NH₃H₂O / M2 186

/ NH₃H₂O / M2 187

/ NH₃H₂O / M4 188

/ / / M2 189

/ / / M2 190

/ / / M2 191

/ / / M2 192

/ / / M2 193

/ / / M2 194

/ / / M2 195

/ / / M2 196

/ / / M4 197

/ NH₃H₂O / M2 198

/ NH₃H₂O / M2 199

/ / / M2 200

/ NH₃H₂O / M2 201

/ NH₃H₂O / M2   202a

/ NH₃H₂O Method 8 M2  202b

/ NH₃H₂O Method 8 M2 203

/ NH₃H₂O / M2   204a

/ NH₄HCO₃ Method 5 M2  204b

/ NH₄HCO₃ Method 5 M2

Compound 5:N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-(oxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₅S 394.10, m/z found 395.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (br.s., 1H), 8.51 (br. s.,1H), 7.95 (d, J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 7.65-7.60 (m,1H), 7.58-7.52 (m, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.13 (t, J=9.2 Hz, 1H),4.51 (t, J=6.8 Hz, 2H), 4.41-4.32 (m, 1H), 4.25 (t, J=6.8 Hz, 2H), 3.96(s, 3H), 2.24 (s, 3H).

Compound 6a:N-(4-Fluoro-3-methylphenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (br.s, 1H), 7.95 (d, J=2.4 Hz,1H), 7.90-7.83 (m, 2H), 7.65-7.61 (m, 1H), 7.58-7.52 (m, 1H), 7.36 (d,J=8.8 Hz, 1H), 7.13 (t, J=9.6 Hz, 1H), 4.95 (d, J=5.2 Hz, 1H), 4.16-4.09(m, 1H), 3.97 (s, 3H), 3.75-3.64 (m, 1H), 2.24 (s, 3H), 2.00-1.86 (m,4H).

Compound 6b:N-(4-Fluoro-3-methylphenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (br.s, 1H), 7.97 (d, J=2.4 Hz,1H), 7.89-7.82 (m, 2H), 7.65-7.61 (m, 1H), 7.58-7.53 (m, 1H), 7.36 (d,J=8.8 Hz, 1H), 7.13 (t, J=9.0 Hz, 1H), 5.02 (d, J=5.5 Hz, 1H), 3.97 (s,3H), 3.69-3.62 (m, 1H), 3.14-3.03 (m, 1H), 2.27-2.29 (m, 5H), 1.61-1.53(m, 2H).

Compound 7:N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-(3-methylcyclobutyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₄S 406.14, m/z found 407.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1H), 7.97 (d, J=2.21 Hz,1H), 7.95-7.82 (m, 2H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 1H), 7.35 (d,J=9.04 Hz, 1H), 7.13 (t, J=9.26 Hz, 1H), 3.97 (s, 3H), 3.81-3.73 (m, 1H,trans), 3.47-3.42 (m, 1H, cis), 2.24 (s, 3H), 2.15-2.05 (m, 3H, cis),1.96-1.82 (m, 3H, trans), 1.68-1.59 (m, 1H), 1.37-1.27 (m, 1H), 1.00 (d,J=1.00 Hz, 1.5H), 0.91 (d, J=6.62 Hz, 1.5H).

Compound 7a:N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-((cis)-3-methylcyclobutyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₄S 406.14, m/z found 407.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (s, 1H), 7.95 (d, J=2.21 Hz,1H), 7.86 (dd, J=8.82, 2.43 Hz, 1H), 7.84-7.76 (m, 1H), 7.64-7.58 (m,1H), 7.54 (m, 1H), 7.33 (d, J=8.82 Hz, 1H), 7.11 (t, J=9.15 Hz, 1H),3.94 (s, 3H), 3.43-3.38 (m, 1H), 2.22 (s, 3H), 2.13-2.02 (m, 2H),1.86-1.75 (m, 1H), 1.35-1.25 (m, 2H), 0.89 (d, J=6.39 Hz, 3H).

Compound 7b:N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-((trans)-3-methylcyclobutyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₄S 406.14, m/z found 407.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (s, 1H), 7.96 (d, J=2.01 Hz,1H), 7.91 (m, J=7.50 Hz, 1H), 7.87 (dd, J=8.53, 2.51 Hz, 1H), 7.66-7.60(m, 1H), 7.58-7.51 (m, 1H), 7.35 (d, J=9.03 Hz, 1H), 7.12 (t, J=9.03 Hz,1H), 3.96 (s, 3H), 3.82-3.70 (m, 1H), 2.23 (s, 3H), 2.12 (m, 1H),1.95-1.85 (m, 2H), 1.68-1.58 (m, 2H), 0.99 (d, J=7.03 Hz, 3H).

Compound 8:N-(4-Fluoro-3-methylphenyl)-5-(N-isopropylsulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₁FN₂O₄S 380.12, m/z found 381.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 8.00 (d, J=2.4 Hz,1H), 7.91 (dd, J=2.3, 8.7 Hz, 1H), 7.66-7.61 (m, 1H), 7.60-7.52 (m, 2H),7.37 (d, J=8.8 Hz, 1H), 7.13 (t, J=9.3 Hz, 1H), 3.97 (s, 3H), 3.27-3.17(m, 1H), 2.24 (s, 3H), 0.97 (d, J=6.4 Hz, 6H).

Compound 9:N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-(3-methyloxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 8.33 (s, 1H), 8.00(d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 8.8 Hz, 1H), 7.63 (dd, J=2.2, 7.1Hz, 1H), 7.59-7.52 (m, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.13 (t, J=9.2 Hz,1H), 4.54 (d, J=6.0 Hz, 2H), 4.12 (d, J=6.2 Hz, 2H), 3.97 (s, 3H), 2.24(s, 3H), 1.43 (s, 3H).

Compound 10:N-(4-Fluoro-3-methylphenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₁FN₂O₅S 396.12, m/z found 397.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d) δ 10.21 (s, 1H), 8.01 (d, J=2.4 Hz,1H), 7.92 (dd, J=2.3, 8.7 Hz, 1H), 7.67-7.60 (m, 1H), 7.59-7.49 (m, 2H),7.36 (d, J=8.8 Hz, 1H), 7.13 (t, J=9.2 Hz, 1H), 4.73 (t, J=5.4 Hz, 1H),3.97 (s, 3H), 3.34-3.28 (m, 1H), 3.16-3.02 (m, 2H), 2.24 (s, 3H), 0.91(d, J=6.2 Hz, 3H).

Compound 10a:(S)—N-(4-Fluoro-3-methylphenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₁FN₂O₅S 396.12, m/z found 397.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d) δ 10.21 (s, 1H), 8.01 (d, J=2.2 Hz,1H), 7.92 (dd, J=2.2, 8.8 Hz, 1H), 7.66-7.60 (m, 1H), 7.59-7.48 (m, 2H),7.36 (d, J=9.0 Hz, 1H), 7.13 (t, J=9.2 Hz, 1H), 4.71 (t, J=5.4 Hz, 1H),3.97 (s, 3H), 3.34-3.26 (m, 1H), 3.15-3.02 (m, 2H), 2.24 (s, 3H), 0.91(d, J=6.0 Hz, 3H).

Compound 10b:(R)—N-(4-Fluoro-3-methylphenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamideCompound 11a:(S*)-5-(N-(1-Cyanopropan-2-yl)sulfamoyl)-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀FN₃O₄S 405.12, m/z found 406.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.20 (s, 1H), 8.02 (d, J=2.2 Hz, 2H),7.94 (dd, J=2.4, 8.8 Hz, 1H), 7.63 (dd, J=2.1, 7.0 Hz, 1H), 7.58-7.52(m, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.12 (t, J=9.2 Hz, 1H), 3.97 (s, 3H),3.46-3.38 (m, 1H), 2.76-2.66 (m, 1H), 2.66-2.57 (m, 1H), 2.24 (s, 3H),1.00 (d, J=6.6 Hz, 3H).

Compound 11b:(R*)-5-(N-(1-Cyanopropan-2-yl)sulfamoyl)-N-(4-fluoro-3-methylphenyl-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀FN₃O₄S 405.12, m/z found 406.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.03 (br. s., 1H),8.01 (d, J=2.4 Hz, 1H), 7.94 (dd, J=2.4, 8.8 Hz, 1H), 7.66-7.60 (m, 1H),7.59-7.50 (m, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.12 (t, J=9.2 Hz, 1H), 3.97(s, 3H), 3.47-3.39 (m, 1H), 2.75-2.66 (m, 1H), 2.66-2.57 (m, 1H), 2.24(s, 3H), 1.00 (d, J=6.6 Hz, 3H).

Compound 12:5-(N-(1-Amino-1-oxopropan-2-yl)sulfamoyl)-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₅S 409.11, m/z found 410.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.00 (d, J=2.2 Hz,1H), 7.90 (dd, J=2.4, 8.8 Hz, 1H), 7.87 (br. s., 1H), 7.66-7.60 (m, 1H),7.59-7.52 (m, J=4.0, 7.9 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.29 (br. s.,1H), 7.13 (t, J=9.3 Hz, 1H), 7.00 (br. s., 1H), 3.96 (s, 3H), 3.67 (q,J=6.8 Hz, 1H), 2.24 (s, 3H), 1.07 (d, J=7.1 Hz, 3H).

Compound 12a:(S)-5-(N-(1-Amino-1-oxopropan-2-yl)sulfamoyl)-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₅S 409.11, m/z found 410.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.01 (d, J=2.2 Hz,1H), 7.95-7.84 (m, 2H), 7.67-7.60 (m, 1H), 7.59-7.51 (m, 1H), 7.35 (d,J=8.8 Hz, 1H), 7.29 (br. s., 1H), 7.13 (t, J=9.2 Hz, 1H), 7.00 (br. s.,1H), 3.96 (s, 3H), 3.74-3.61 (m, J=4.9 Hz, 1H), 2.24 (s, 3H), 1.08 (d,J=7.1 Hz, 3H).

Compound 12b:(R)-5-(N-(1-Amino-1-oxopropan-2-yl)sulfamoyl)-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₅S 409.11, m/z found 410.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.00 (d, J=2.2 Hz,1H), 7.93-7.86 (m, 2H), 7.63 (dd, J=2.0, 6.8 Hz, 1H), 7.59-7.52 (m, 1H),7.35 (d, J=9.0 Hz, 1H), 7.29 (br. s., 1H), 7.13 (t, J=9.3 Hz, 1H), 7.00(br. s., 1H), 3.96 (s, 3H), 3.68 (q, J=6.9 Hz, 1H), 2.24 (s, 3H), 1.07(d, J=7.1 Hz, 3H).

Compound 13:N-(4-Fluoro-3-methylphenyl)-5-(N-(3-(hydroxymethyl)oxetan-3-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₆S 424.11, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1H), 8.31 (br. s., 1H),8.02 (d, J=2.0 Hz, 1H), 7.94 (dd, J=2.3, 8.8 Hz, 1H), 7.66-7.60 (m, 1H),7.59-7.52 (m, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.13 (t, J=9.3 Hz, 1H), 5.17(t, J=5.5 Hz, 1H), 4.47 (d, J=6.5 Hz, 2H), 4.36 (d, J=6.0 Hz, 2H), 3.97(s, 3H), 3.52 (d, J=5.5 Hz, 2H), 2.24 (s, 3H).

Compound 14:5-(N-(3,3-Dimethylcyclobutyl)sulfamoyl)-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. For C₂₁H₂₅FN₂O₄S 420.15, m/z found 421.0[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (s, 1H), 7.96 (d, J=2.0 Hz,1H), 7.88 (dd, J=2.3, 8.8 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.66-7.60 (m,1H), 7.58-7.51 (m, 1H), 7.35 (d, J=9.0 Hz, 1H), 7.12 (t, J=9.3 Hz, 1H),3.96 (s, 3H), 3.70-3.54 (m, 1H), 2.24 (s, 3H), 1.86-1.72 (m, 2H),1.61-1.47 (m, 2H), 0.99 (s, 3H), 0.97 (s, 3H).

Compound 15a:N-(4-Fluoro-3-methylphenyl)-5-(N-((cis)-3-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₅S 422.13, m/z found 423.0[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.00 (d, J=2.0 Hz,1H), 7.90 (dd, J=2.0, 8.8 Hz, 1H), 7.64 (t, J=8.8 Hz, 2H), 7.59-7.51 (m,1H), 7.36 (d, J=8.8 Hz, 1H), 7.12 (t, J=9.2 Hz, 1H), 4.57 (d, J=3.9 Hz,1H), 3.97 (s, 3H), 3.94-3.87 (m, 1H), 2.24 (s, 3H), 1.98-1.86 (m, 1H),1.64-1.49 (m, 2H), 1.49-1.37 (m, 2H), 1.27-1.16 (m, 1H).

Compound 15b:N-(4-Fluoro-3-methylphenyl)-5-(N-((cis)-3-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₅S 422.13, m/z found 423.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 8.01 (d, J=1.5 Hz,1H), 7.95-7.87 (m, 1H), 7.70-7.60 (m, 2H), 7.59-7.51 (m, 1H), 7.36 (d,J=8.5 Hz, 1H), 7.13 (t, J=9.0 Hz, 1H), 4.65 (d, J=4.0 Hz, 1H), 3.97 (s,3H), 3.95-3.88 (m, 1H), 2.24 (s, 3H), 1.98-1.88 (m, 1H), 1.64-1.38 (m,4H), 1.28-1.17 (m, 1H).

Compound 16a:(S*)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(tetrahydro-2H-pyran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₅S 423.13, m/z found 424.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.14 (d, J=2.3 Hz,1H), 8.11-8.06 (m, 1H), 7.95 (dd, J=2.5, 8.8 Hz, 1H), 7.81 (br. s., 1H),7.71 (t, J=8.9 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.01 (s, 3H), 3.64-3.53(m, 2H), 3.24-3.15 (m, 1H), 3.06-2.94 (m, 2H), 2.40 (d, J=2.8 Hz, 3H),1.69-1.53 (m, 2H), 1.44-1.28 (m, 2H).

Compound 16b:(R*)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(tetrahydro-2H-pyran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₅S 423.13, m/z found 424.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.14 (d, J=2.5 Hz,1H), 8.12-8.07 (m, 1H), 7.95 (dd, J=2.5, 8.8 Hz, 1H), 7.83-7.78 (m, 1H),7.71 (t, J=9.0 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 4.01 (s, 3H), 3.63-3.54(m, 2H), 3.24-3.16 (m, 1H), 3.06-2.94 (m, 2H), 2.41 (d, J=3.0 Hz, 3H),1.70-1.53 (m, 2H), 1.42-1.27 (m, 2H).

Compound 17:N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(tetrahydro-2H-pyran-4-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₅S 423.13, m/z found 424.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.16 (d, J=2.3 Hz,1H), 8.13-8.07 (m, 1H), 7.95 (dd, J=2.5, 8.8 Hz, 1H), 7.80 (d, J=7.0 Hz,1H), 7.71 (t, J=8.9 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.02 (s, 3H),3.76-3.68 (m, 2H), 3.27-3.21 (m, 2H), 3.16 (d, J=4.8 Hz, 1H), 2.41 (d,J=2.8 Hz, 3H), 1.54 (d, J=10.8 Hz, 2H), 1.42-1.30 (m, 2H).

Compound 18:(trans)-N-(5-Fluoro-6-methylpyridin-2-yl)-5-(N-(−4-hydroxycyclohexyl)sulfamoyl)-2-methoxybenzamid

LC-MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₅S 437.14, m/z found 438.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.14 (d, J=2.4 Hz,1H), 8.12-8.07 (m, 1H), 7.93 (dd, J=2.4, 8.8 Hz, 1H), 7.71 (t, J=9.0 Hz,1H), 7.62 (d, J=7.0 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 4.49 (d, J=4.3 Hz,1H), 4.01 (s, 3H), 3.29-3.26 (m, 1H), 2.92-2.81 (m, 1H), 2.41 (d, J=2.8Hz, 3H), 1.74-1.66 (m, 2H), 1.64-1.57 (m, 2H), 1.19-1.02 (m, 4H).

Compound 19:N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(1-methylpiperidin-4-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₅FN₄O₄S 436.16, m/z found 437.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.16 (d, J=2.3 Hz,1H), 8.09 (d, J=5.5 Hz, 1H), 7.94 (dd, J=2.4, 8.7 Hz, 1H), 7.74-7.64 (m,2H), 7.39 (d, J=8.8 Hz, 1H), 4.02 (s, 3H), 2.94-2.83 (m, 1H), 2.63-2.56(m, 2H), 2.41 (d, J=2.8 Hz, 3H), 2.08 (s, 3H), 1.86-1.76 (m, 2H),1.58-1.49 (m, 2H), 1.44-1.32 (m, 2H).

Compound 20:5-(N-Cyclohexylsulfamoyl)-N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₄S 421.15, m/z found 422.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.16 (s, 1H),8.13-8.07 (m, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.71 (t, J=8.7 Hz, 1H), 7.64(d, J=7.3 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 4.02 (s, 3H), 2.98-2.87 (m,1H), 2.41 (d, J=2.3 Hz, 3H), 1.64-1.53 (m, 4H), 1.48-1.40 (m, 1H),1.19-1.01 (m, 5H).

Compound 21:5-(N-Cyclopropylsulfamoyl)-N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈FN₃O₄S 379.10, m/z found 380.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.15 (d, J=2.0 Hz,1H), 8.13-8.07 (m, 1H), 7.96-7.89 (m, 2H), 7.71 (t, J=9.0 Hz, 1H), 7.42(d, J=8.8 Hz, 1H), 4.02 (s, 3H), 2.41 (d, J=2.8 Hz, 3H), 2.14-2.06 (m,1H), 0.52-0.45 (m, 2H), 0.42-0.35 (m, 2H).

Compound 22:N-(5-Fluoro-6-methylpyridin-2-yl-2-methoxy-5-sulfamoylbenzamide

LC-MS (ESI): mass calcd. for C₁₄H₁₄FN₃O₄S 339.07, m/z found 340.0[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (br.s, 1H), 8.21 (s, 1H), 8.11(d, J=6.4 Hz, 1H), 7.95 (m, J=7.6 Hz, 1H), 7.71 (t, J=9.2 Hz, 1H),7.33-7.43 (m, 3H), 4.02 (s, 3H), 2.41 (s, 3H).

Compound 23a:(R*)—N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₇F₄N₃O₅S 451.08, m/z found 452.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d) δ 10.60 (br.s, 1H), 8.07-8.15 (m, 2H),7.91-8.00 (m, 2H), 7.72 (t, J=9.2 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 6.63(s, 1H), 4.01 (s, 4H), 2.98 (dd, J=13.6 Hz, J=4.0 Hz, 1H), 2.82 (dd,J=13.6 Hz, J=8.0 Hz, 1H), 2.41 (d, J=2.4 Hz, 3H).

Compound 23b:(S*)—N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇F₄N₃O₅S 451.08, m/z found 452.1[M+H]⁺¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (br.s, 1H), 8.07-8.16 (m, 2H),7.91-8.01 (m, 2H), 7.72 (t, J=8.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 6.63(s, 1H), 4.01 (s, 4H), 2.98 (dd, J=13.6 Hz, J=4.0 Hz, 1H), 2.82 (dd,J=13.6 Hz, J=8.0 Hz, 1H), 2.41 (d, J=2.4 Hz, 3H).

Compound 24:N-(5-Fluoro-6-methylpyridin-2-yl-2-methoxy-5-(N-methylsulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₅H₁₆FN₃O₄S 353.08, m/z found 354.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) 10.61 (br.s, 1H), 8.12-8.07 (m, 2H),7.91 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.71 (t, J=8.8 Hz, 1H), 7.48-7.38 (m,2H), 4.01 (s, 3H), 2.44-2.36 (m, 6H).

Compound 25:N-(5-Fluoro-6-methylpyridin-2-yl)-5-(N-isopropylsulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₂₀FN₃O₄S 381.12, m/z found 382.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.58 (s, 1H), 8.19-8.05 (m, 2H), 7.93(dd, J=2.5, 8.5 Hz, 1H), 7.71 (t, J=9.0 Hz, 1H), 7.59 (d, J=7.0 Hz, 1H),7.39 (d, J=8.5 Hz, 1H), 4.01 (s, 3H), 3.30-3.15 (m, 1H), 2.40 (d, J=2.5Hz, 3H), 0.96 (d, J=6.5 Hz, 6H).

Compound 26:5-(N-Ethylsulfamoyl)-N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₆H₁₈FN₃O₄S 367.10, m/z found 368.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) 10.59 (br.s, 1H), 8.15-8.05 (m, 2H),7.91 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.71 (t, J=8.8 Hz, 1H), 7.55 (t,J=5.6 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.01 (s, 3H), 2.80-2.70 (m, 2H),2.40 (d, J=2.8 Hz, 3H), 0.98 (t, J=7.2 Hz, 3H).

Compound 27:N-(5-Fluoro-6-methylpyridin-2-yl)-5-(N-((cis)-4-hydroxycyclohexyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₅S 437.14, m/z found 438.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.21-8.00 (m, 2H),7.92 (s, 1H), 7.80-7.50 (m, 2H), 7.36 (d, J=7.1 Hz, 1H), 4.40-4.25 (m,1H), 3.99 (s, 3H), 3.60-3.50 (m, 1H), 3.00-2.90 (m, 1H), 2.39 (s, 3H),1.60-1.40 (m, 4H), 1.40-1.20 (m, 4H).

Compound 28a:N-(5-Fluoro-6-methylpyridin-2-yl)-5-(N-((trans)-2-hydroxycyclohexyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₄S 437.14, m/z found 438.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.19 (d, J=2.4 Hz,1H), 8.15-8.05 (m, 1H), 7.96 (dd, J=8.8, 2.5 Hz, 1H), 7.71 (t, J=9.0 Hz,1H), 7.52-7.42 (m, 1H), 7.36 (d, J=8.9 Hz, 1H), 4.50 (d, J=4.6 Hz, 1H),4.01 (s, 3H), 3.25-3.15 (m, 1H), 2.82-2.72 (m, 1H), 2.41 (d, J=2.8 Hz,3H), 1.80-1.72 (m, 1H), 1.70-1.62 (m, 1H), 1.56-1.42 (m, 2H), 1.19-1.02(m, 4H).

Compound 28b:N-(5-Fluoro-6-methylpyridin-2-yl)-5-(N-((trans)-2-hydroxycyclohexyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₄FN₃O₅S 437.14, m/z found 438.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.19 (d, J=2.4 Hz,1H), 8.15-8.05 (m, 1H), 7.96 (dd, J=8.8, 2.5 Hz, 1H), 7.71 (t, J=9.0 Hz,1H), 7.52-7.42 (m, 1H), 7.36 (d, J=8.9 Hz, 1H), 4.50 (d, J=4.6 Hz, 1H),4.01 (s, 3H), 3.25-3.15 (m, 1H), 2.82-2.72 (m, 1H), 2.41 (d, J=2.8 Hz,3H), 1.80-1.72 (m, 1H), 1.70-1.62 (m, 1H), 1.56-1.42 (m, 2H), 1.19-1.02(m, 4H).

Compound 29a:(S*)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇F₄N₃O₄S 435.09, m/z found 436.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.50 (d, J=8.8 Hz,1H), 8.16 (d, J=2.0 Hz, 1H), 8.10 (d, J=6.2 Hz, 1H), 7.98 (dd, J=2.4,8.8 Hz, 1H), 7.72 (t, J=8.9 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 4.12-4.04(m, 1H), 4.02 (s, 3H), 2.41 (d, J=2.4 Hz, 3H), 1.01 (d, J=7.1 Hz, 3H).

Compound 29b:(R*)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇F₄N₃O₄S 435.09, m/z found 436.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.50 (d, J=5.3 Hz,1H), 8.16 (d, J=2.2 Hz, 1H), 8.10 (d, J=6.4 Hz, 1H), 7.98 (dd, J=2.4,8.8 Hz, 1H), 7.72 (t, J=9.0 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 4.13-4.04(m, J=6.6 Hz, 1H), 4.02 (s, 3H), 2.41 (d, J=2.4 Hz, 3H), 1.01 (d, J=6.8Hz, 3H).

Compound 30:N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(pyrrolidin-1-ylsulfonyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₄S 393.43, m/z found 394.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (br.s, 1H), 8.09 (d, J=6.8 Hz,1H), 8.02 (s, 1H), 7.94 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.71 (t, J=8.8 Hz,1H), 7.41 (d, J=4.8 Hz, 1H), 4.00 (s, 3H), 3.49-3.05 (m, 4H), 2.45-2.35(m, 3H), 1.73-1.60 (m, 4H).

Compound 31:N-(5-fluoro-6-methylpyridin-2-yl)-5-(N-((cis)-3-hydroxy-3-methylcyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₅S 423.13, m/z found 424.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.12 (d, J=2.0 Hz,1H), 8.11-8.05 (m, 1H), 7.89 (dd, J=2.3, 8.8 Hz, 1H), 7.85 (d, J=7.3 Hz,1H), 7.70 (t, J=9.0 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.89 (s, 1H), 4.00(s, 3H), 3.23-3.12 (m, 1H), 2.39 (d, J=2.5 Hz, 3H), 2.01-1.93 (m, 2H),1.81-1.72 (m, 2H), 1.09 (s, 3H).

Compound 32a:(R*)—N-(3-(Difluoromethyl)-4-fluorophenyl)-2-methoxy-5-(N-(1-methoxypropan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁F₃N₂O₅S 446.11, m/z found 447.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.07 (d, J=4.4 Hz,1H), 8.01 (d, J=2.0 Hz, 1H), 7.93 (dd, J=2.4, 8.8 Hz, 1H), 7.90-0.783(m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.43-7.33 (m, 2H), 7.24 (t, J=54.4 Hz,1H), 3.96 (s, 3H), 3.29-3.07 (m, 3H), 3.14 (s, 3H), 0.91 (d, J=6.8 Hz,3H).

Compound 32b:(S*)—N-(3-(Difluoromethyl)-4-fluorophenyl)-2-methoxy-5-(N-(1-methoxypropan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁F₃N₂O₅S 446.11, m/z found 447.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.07 (d, J=4.0 Hz,1H), 8.01 (d, J=2.0 Hz, 1H), 7.93 (dd, J=2.4, 8.8 Hz, 1H), 7.83-7.89 (m,1H), 7.68 (d, J=7.2 Hz, 1H), 7.43-7.34 (m, 2H), 7.24 (t, J=54.0 Hz, 1H),3.96 (s, 3H), 3.22-3.07 (m, 3H), 3.14 (s, 3H), 0.92 (d, J=6.8 Hz, 3H).

Compound 33a:N-(3-(Difluoromethyl)-4-fluorophenyl)-5-(N-((cis)-3-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₁F₃N₂O₅S 458.11, m/z found 459.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.11-8.05 (m, 1H),8.00 (d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 8.8 Hz, 1H), 7.90-7.83 (m, 1H),7.67 (d, J=7.2 Hz, 1H), 7.43-7.35 (m, 2H), 7.24 (t, J=54.4 Hz, 1H), 4.60(d, J=4.0 Hz, 1H), 3.97 (s, 3H), 3.91 (dd, J=4.6, 9.8 Hz, 1H), 1.96-1.88(m, 1H), 1.60-1.41 (m, 4H), 1.28-1.18 (m, 2H).

Compound 33b:N-(3-(Difluoromethyl)-4-fluorophenyl)-5-(N-((cis)-3-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₁F₃N₂O₅S 458.11, m/z found 459.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.11-8.05 (m, 1H),8.00 (d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 8.8 Hz, 1H), 7.89-7.84 (m, 1H),7.67 (d, J=7.2 Hz, 1H), 7.43-7.35 (m, 2H), 7.24 (t, J=54.4 Hz, 1H), 4.60(d, J=4.4 Hz, 1H), 3.97 (s, 3H), 3.92 (dd, J=4.4, 10.4 Hz, 1H),1.96-1.89 (m, 1H), 1.60-1.41 (m, 4H), 1.31-1.17 (m, 2H).

Compound 34a:(S)-5-(N-(1-Amino-1-oxopropan-2-yl)sulfamoyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₃N₃O₅S 445.09, m/z found 446.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.09 (dd, J=2.4, 6.4Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 8.8 Hz, 1H), 7.89-7.85(m, 2H), 7.42-7.33 (m, 3H), 7.24 (t, J=54.4 Hz, 1H), 6.99 (s, 1H), 3.96(s, 3H), 3.68 (q, J=6.8 Hz, 1H), 1.09 (d, J=6.8 Hz, 3H).

Compound 34b:(R)-5-(N-(1-Amino-1-oxopropan-2-yl)sulfamoyl)-N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₃N₃O₅S 445.09, m/z found 446.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.08 (dd, J=2.4, 6.4Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 8.8 Hz, 1H), 7.89-7.85(m, 2H), 7.41-7.35 (m, 3H), 7.24 (t, J=54.4 Hz, 1H), 6.99 (s, 1H), 3.96(s, 3H), 3.68 (t, J=5.6, 6.8 Hz, 1H), 1.08 (d, J=7.2 Hz, 3H).

Compound 35a:(S)—N-(3-(Difluoromethyl)-4-fluorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉F₃N₂O₅S 432.10, m/z found 433.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.08 (dd, J=2.4, 6.4Hz, 1H), 8.01 (d, J=2.8 Hz, 1H), 7.93 (dd, J=2.4, 8.8 Hz, 1H), 7.89-7.84(m, 1H), 7.53 (d, J=6.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.24 (t, J=54.4 Hz,1H), 4.71 (t, J=5.2, 6 Hz, 1H), 3.96 (s, 3H), 3.14-3.05 (m, 2H), 0.91(d, J=6.4 Hz, 3H).

Compound 35b:(R)—N-(3-(Difluoromethyl)-4-fluorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉F₃N₂O₅S 432.10, m/z found 433.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.08 (dd, J=2.4, 6.4Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 8.8 Hz, 1H), 7.88-7.84(m, 1H), 7.53 (d, J=6.0 Hz, 1H), 7.42-7.36 (m, 2H), 7.24 (t, J=54.4 Hz,1H), 4.71 (t, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.14-3.08 (m, 2H), 0.91 (d,J=6.0 Hz, 3H).

Compound 36:N-(3-(Difluoromethyl)-4-fluorophenyl)-2-methoxy-5-(N-(3-methyloxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₅S 444.10, m/z found 445.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 8.37 (s, 1H), 8.08(dd, J=2.4, 6.2 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 8.8Hz, 1H), 7.90-7.83 (m, 1H), 7.42-7.09 (m, 3H), 4.54 (d, J=6.0 Hz, 2H),4.12 (d, J=6.4 Hz, 2H), 3.96 (s, 3H), 1.43 (s, 3H).

Compound 37:(S)—N-(3-(Difluoromethyl)-4-fluorophenyl)-2-methoxy-5-(N-(tetrahydro-2H-pyran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₁F₃N₂O₅S 458.11, m/z found 459.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.07 (d, J=4.0 Hz,1H), 8.01 (d, J=2.0 Hz, 1H), 7.95 (dd, J=2.5, 9.0 Hz, 1H), 7.89-7.83 (m,1H), 7.80 (d, J=7.0 Hz, 1H), 7.42-7.35 (m, 2.25H), 7.24 (s, 0.50H), 7.11(s, 0.26H), 3.97 (s, 3H), 3.65-3.54 (m, 2H), 3.26-3.16 (m, 1H),3.08-2.94 (m, 2H), 1.71-1.54 (m, 2H), 1.45-1.28 (m, 2H).

Compound 38:N-(3-(Difluoromethyl)-4-fluorophenyl)-5-(N-((cis)-4-hydroxycyclohexyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₅S 472.13, m/z found 473.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.11-8.04 (m, 1H),8.04-7.98 (m, 1H), 7.96-7.90 (m, 1H), 7.89-7.82 (m, 1H), 7.67-7.54 (m,1H), 7.42-7.34 (m, 1H), 7.24 (s, 1H), 7.10 (s, 1H), 3.96 (s, 3H),3.60-3.54 (m, 2H), 3.00-2.92 (m, 1H), 1.61-1.44 (m, 4H), 1.41-1.27 (m,4H).

Compound 39:N-(3-(Difluoromethyl)-4-fluorophenyl)-2-methoxy-5-(N-(oxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇F₃N₂O₅S 430.08, m/z found 431.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 8.56 (d, J=8.0 Hz,1H), 8.11-8.04 (m, 1H), 7.98-7.94 (m, J=2.5 Hz, 1H), 7.92-7.84 (m, 2H),7.44-7.33 (m, 2H), 7.33-7.10 (m, 1H), 4.51 (t, J=6.5 Hz, 2H), 4.43-4.32(m, 1H), 4.31-4.25 (m, 2H), 3.96 (s, 3H).

Compound 40a:(S*)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(1-methoxypropan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₁FN₂O₅S 396.12, m/z found 397.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.00 (d, J=2.5 Hz,1H), 7.92 (dd, J=2.5, 8.8 Hz, 1H), 7.77-7.72 (m, 2H), 7.68 (d, J=7.0 Hz,1H), 7.35 (d, J=8.8 Hz, 1H), 7.20 (t, J=8.9 Hz, 2H), 3.96 (s, 3H),3.30-3.23 (m, 1H), 3.23-3.18 (m, 1H), 3.14 (s, 3H), 3.12-3.07 (m, 1H),0.91 (d, J=6.5 Hz, 3H).

Compound 40b:(R*)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(1-methoxypropan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₁FN₂O₅S 396.12, m/z found 397.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.00 (d, J=2.5 Hz,1H), 7.92 (dd, J=2.5, 8.8 Hz, 1H), 7.77-7.72 (m, 2H), 7.68 (d, J=7.3 Hz,1H), 7.36 (d, J=8.8 Hz, 1H), 7.23-7.17 (m, 2H), 3.96 (s, 3H), 3.27 (td,J=6.4, 12.6 Hz, 1H), 3.23-3.17 (m, 1H), 3.14 (s, 3H), 3.12-3.06 (m, 1H),0.91 (d, J=6.5 Hz, 3H).

Compound 41:(S)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(tetrahydro-2H-pyran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.00 (d, J=2.3 Hz,1H), 7.94 (dd, J=2.5, 8.8 Hz, 1H), 7.83-7.71 (m, 3H), 7.37 (d, J=9.0 Hz,1H), 7.20 (t, J=8.9 Hz, 2H), 3.96 (s, 3H), 3.64-3.54 (m, 2H), 3.25-3.17(m, 1H), 3.07-2.93 (m, 2H), 1.71-1.52 (m, 2H), 1.44-1.27 (m, 2H).

Compound 42:N-(4-Fluorophenyl)-2-methoxy-5-(N-(3-methyloxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₅S 394.10, m/z found 395.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.30 (br. s., 1H),8.00 (d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 8.8 Hz, 1H), 7.78-7.71 (m, 2H),7.37 (d, J=8.8 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 4.54 (d, J=6.0 Hz, 2H),4.12 (d, J=6.4 Hz, 2H), 3.97 (s, 3H), 1.43 (s, 3H).

Compound 43:N-(4-Fluorophenyl)-2-methoxy-5-(N-(oxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇FN₂O₅S 380.08, m/z found 381.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.51 (d, J=6.8 Hz,1H), 7.95 (d, J=2.5 Hz, 1H), 7.88 (dd, J=2.5, 8.8 Hz, 1H), 7.77-7.71 (m,2H), 7.36 (d, J=8.8 Hz, 1H), 7.24-7.17 (m, 2H), 4.51 (t, J=6.8 Hz, 2H),4.42-4.32 (m, 1H), 4.30-4.24 (m, 2H), 3.96 (s, 3H).

Compound 44a(S*)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₆F₄N₂O₅S 436.07, m/z found 437.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.02-7.90 (m, 3H),7.78-7.70 (m, 2H), 7.38 (d, J=9.0 Hz, 1H), 7.21 (t, J=8.9 Hz, 2H), 6.64(d, J=6.0 Hz, 1H), 4.04 (br. s., 1H), 3.97 (s, 3H), 3.03-2.94 (m, 1H),2.86-2.77 (m, 1H).

Compound 44b:(R*)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₆F₄N₂O₅S 436.07, m/z found 437.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.02-7.89 (m, 3H),7.79-7.71 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.21 (t, J=8.9 Hz, 2H), 6.64(d, J=6.3 Hz, 1H), 4.10-3.99 (m, 1H), 3.97 (s, 3H), 3.02-2.94 (m, 1H),2.86-2.77 (m, 1H).

Compound 45a:N-(4-Fluorophenyl)-5-(N-((cis)-3-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.29 (s, 1H), 7.99 (d, J=2.0 Hz, 1H),7.91 (dd, J=2.3, 8.8 Hz, 1H), 7.75 (dd, J=5.0, 8.5 Hz, 2H), 7.66 (d,J=7.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 4.59 (d,J=4.0 Hz, 1H), 3.96 (s, 3H), 3.94-3.86 (m, J=4.8, 9.8 Hz, 1H), 1.96-1.86(m, 1H), 1.64-1.37 (m, 4H), 1.25-1.17 (m, 1H).

Compound 45b: N-(4-Fluorophenyl)-5-(N-((cis)-3-hydroxycyclopentylsulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.29 (s, 1H), 7.99 (d, J=2.5 Hz, 1H),7.91 (dd, J=2.3, 8.8 Hz, 1H), 7.75 (dd, J=5.0, 9.0 Hz, 2H), 7.66 (d,J=6.5 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 4.59 (d,J=4.0 Hz, 1H), 3.96 (s, 3H), 3.94-3.86 (m, 1H), 3.34-3.29 (m, 1H),1.97-1.86 (m, 1H), 1.63-1.37 (m, 4H), 1.25-1.17 (m, 1H).

Compound 46a:(R)-5-(N-(1-Amino-1-oxopropan-2-yl)sulfamoyl)-N-(4-fluorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈FN₃O₅S 395.10, m/z found 396.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.28 (s, 1H), 8.00 (d, J=2.2 Hz, 1H),7.95-7.85 (m, 2H), 7.75 (dd, J=5.1, 8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 1H),7.31 (br. s., 1H), 7.21 (t, J=8.8 Hz, 2H), 7.01 (br. s., 1H), 3.96 (s,3H), 3.73-3.62 (m, 1H), 1.07 (d, J=7.1 Hz, 3H).

Compound 46b:(S)-5-(N-(1-Amino-1-oxopropan-2-yl)sulfamoyl)-N-(4-fluorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈FN₃O₅S 395.10, m/z found 396.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.27 (s, 1H), 8.00 (d, J=2.0 Hz, 1H),7.94-7.85 (m, 2H), 7.75 (dd, J=5.0, 8.5 Hz, 2H), 7.35 (d, J=9.0 Hz, 1H),7.30 (br. s., 1H), 7.20 (t, J=8.8 Hz, 2H), 7.00 (br. s., 1H), 3.96 (s,3H), 3.68 (q, J=7.0 Hz, 1H), 1.07 (d, J=7.0 Hz, 3H).

Compound 47:5-(N-Cyclobutylsulfamoyl)-N-(4-fluorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₄S 378.10, m/z found 379.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.28 (s, 1H), 7.97 (s, 1H), 7.94 (d,J=8.5 Hz, 1H), 7.91-7.85 (m, 1H), 7.75 (dd, J=5.0, 8.5 Hz, 2H), 7.35 (d,J=8.5 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 3.96 (s, 3H), 3.67-3.56 (m, 1H),1.98-1.85 (m, 2H), 1.81-1.66 (m, 2H), 1.56-1.41 (m, 2H).

Compound 48:5-(N-Cyclopropylsulfamoyl)-N-(4-fluorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇FN₂O₄S 364.09, m/z found 365.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.31 (s, 1H), 7.99 (d, J=2.0 Hz, 1H),7.96-7.86 (m, 2H), 7.74 (dd, J=5.0, 8.5 Hz, 2H), 7.39 (d, J=8.5 Hz, 1H),7.20 (t, J=9.0 Hz, 2H), 3.97 (s, 3H), 2.14-2.05 (m, 1H), 0.54-0.45 (m,2H), 0.43-0.35 (m, 2H).

Compound 49a:(S)—N-(4-Fluorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₉FN₂O₅S 382.10, m/z found 383.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.29 (s, 1H), 8.01 (d, J=2.5 Hz, 1H),7.92 (dd, J=2.3, 8.8 Hz, 1H), 7.75 (dd, J=5.0, 9.0 Hz, 2H), 7.52 (d,J=6.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 4.75-4.68(m, 1H), 3.97 (s, 3H), 3.33-3.27 (m, 1H), 3.16-3.03 (m, 2H), 0.91 (d,J=6.0 Hz, 3H).

Compound 49b:(R)—N-(4-Fluorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₉FN₂O₅S 382.10, m/z found 383.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.30 (s, 1H), 8.01 (d, J=2.0 Hz, 1H),7.92 (dd, J=2.3, 8.8 Hz, 1H), 7.75 (dd, J=5.0, 9.0 Hz, 2H), 7.52 (d,J=5.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.20 (t, J=9.0 Hz, 2H), 4.75-4.67(m, 1H), 3.97 (s, 3H), 3.34-3.27 (m, 1a), 3.15-3.03 (m, 2H), 0.91 (d,J=6.5 Hz, 3H).

Compound 50:N-(4-Fluorophenyl)-2-methoxy-5-(N-(1-(trifluoromethyl)cyclopropyl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₆F₄N₂O₄S 432.08, m/z found 433.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.31 (s, 1H), 9.13 (br. s., 1H), 7.97(d, J=2.4 Hz, 1H), 7.89 (dd, J=2.3, 8.7 Hz, 1H), 7.78-7.72 (m, 2H), 7.37(d, J=8.8 Hz, 1H), 7.21 (t, J=8.9 Hz, 2H), 3.97 (s, 3H), 1.22-1.16 (m,2H), 1.08-0.98 (m, 2H).

Compound 51:5-(N-Cyclopentylsulfamoyl)-N-(4-fluorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₄S 392.12, m/z found 393.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.29 (s, 1H), 7.99 (d, J=2.0 Hz, 1H),7.91 (dd, J=2.3, 8.8 Hz, 1H), 7.79-7.70 (m, 2H), 7.62 (d, J=7.0 Hz, 1H),7.36 (d, J=8.5 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 3.96 (s, 3H), 3.44-3.36(m, 1H), 1.67-1.49 (m, 4H), 1.45-1.25 (m, 4H).

Compound 52a:(S)—N-(4-fluorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₉FN₂O₅S 382.10, m/z found 383.1[M+H]⁺; NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.01 (d, J=2.5 Hz, 1H),7.93 (dd, J=2.3, 8.8 Hz, 1H), 7.80-7.71 (m, 2H), 7.51 (br. s., 1H), 7.37(d, J=9.0 Hz, 1H), 7.20 (t, J=9.0 Hz, 2H), 4.74-4.67 (m, 1H), 3.97 (s,3H), 3.16-3.03 (m, 2H), 0.91 (d, J=6.0 Hz, 3H).

Compound 52b:(R)—N-(4-fluorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₉FN₂O₅S 382.10, m/z found 383.1[M+H]⁺; NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.00 (d, J=2.3 Hz, 1H),7.92 (dd, J=2.1, 8.7 Hz, 1H), 7.75 (dd, J=5.1, 8.9 Hz, 2H), 7.51 (br.s., 1H), 7.36 (d, J=8.8 Hz, 1H), 7.20 (t, J=8.9 Hz, 2H), 4.77-4.66 (m,1H), 3.96 (s, 3H), 3.14-3.04 (m, 2H), 0.91 (d, J=6.0 Hz, 3H).

Compound 53:N-(4-Fluorophenyl)-5-(N-((cis)-4-hydroxycyclohexyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₅S 422.13, m/z found 423.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 8.00 (d, J=2.5 Hz,1H), 7.92 (dd, J=2.5, 8.8 Hz, 1H), 7.77-7.72 (m, 2H), 7.68 (d, J=7.0 Hz,1H), 7.35 (d, J=8.8 Hz, 1H), 7.20 (t, J=8.9 Hz, 2H), 4.36 (s, 1H), 3.97(s, 3H), 3.59 (m, 1H), 2.94 (m, 1H), 1.54 (m, 4H), 1.36 (m, 4H).

Compound 54a:(S*)—N-(2-Chlorophenyl)-2-methoxy-5-(1-methyl-2-oxopyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀ClN₃O₅S 437.08, m/z found 438.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (br. s., 1H), 8.48 (br. s.,1H), 8.39 (d, J=7.8 Hz, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.05 (d, J=8.6 Hz,1H), 7.59 (d, J=7.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.3 Hz,1H), 7.21 (t, J=7.5 Hz, 1H), 4.15 (br. s., 3H), 3.98-3.88 (m, 1H),3.21-3.12 (m, 2H), 2.68 (s, 3H), 2.10-1.99 (m, 1H), 1.64-1.50 (m, 1H).

Compound 54b:(R*)—N-(2-Chlorophenyl)-2-methoxy-5-(N-(1-methyl-2-oxopyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀ClN₃O₅S 437.08, m/z found 438.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (br. s., 1H), 8.48 (br. s.,1H), 8.39 (d, J=7.8 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.6 Hz,1H), 7.59 (d, J=7.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.42 (t, J=7.5 Hz,1H), 7.21 (t, J=7.2 Hz, 1H), 4.15 (br. s., 3H), 3.98-3.88 (m, 1H),3.21-3.11 (m, 2H), 2.67 (s, 3H), 2.10-1.98 (m, 1H), 1.63-1.50 (m, 1H).

Compound 55a:(S)—N-(2-Chlorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₉ClN₂O₅S 398.07, m/z found 399.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.47 (d, J=2.3 Hz,1H), 8.39 (d, J=8.0 Hz, 1H), 8.01 (dd, J=2.4, 8.7 Hz, 1H), 7.65-7.56 (m,2H), 7.49 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.21 (dt, J=1.5,7.7 Hz, 1H), 4.70 (t, J=5.5 Hz, 1H), 4.15 (s, 3H), 3.35-3.26 (m, 1H),3.17-3.04 (m, 2H), 0.90 (d, J=6.3 Hz, 3H).

Compound 55b:(R)—N-(2-Chlorophenyl)-5-(N-(1-hydroxypropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₉ClN₂O₅S 398.07, m/z found 399.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.47 (d, J=2.3 Hz,1H), 8.39 (d, J=8.0 Hz, 1H), 8.01 (dd, J=2.3, 8.8 Hz, 1H), 7.64-7.55 (m,2H), 7.49 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.23-7.17 (m, 1H),4.70 (t, J=5.5 Hz, 1H), 4.15 (s, 3H), 3.34-3.27 (m, 1H), 3.15-3.05 (m,2H), 0.90 (d, J=6.3 Hz, 3H).

Compound 56a:N-(2-Chlorophenyl)-5-(N-((cis)-4-hydroxytetrahydrofuran-3-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₆S 426.07, m/z found 427.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.48 (d, J=2.0 Hz,1H), 8.38 (d, J=8.0 Hz, 1H), 8.05-7.95 (m, 2H), 7.58 (d, J=8.0 Hz, 1H),7.51 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H),5.24 (d, J=4.0 Hz, 1H), 4.15 (s, 3H), 4.01 (br.s., 1H), 3.81-3.70 (m,2H), 3.47-3.39 (m, 3H).

Compound 56b:N-(2-Chlorophenyl)-5-(N-((cis)-4-hydroxytetrahydrofuran-3-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₆S 426.07, m/z found 427.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.48 (d, J=2.5 Hz,1H), 8.38 (d, J=8.3 Hz, 1H), 8.05-7.97 (m, 2H), 7.58 (dd, J=1.3, 8.0 Hz,1H), 7.51 (d, J=9.0 Hz, 1H), 7.41 (t, J=7.3 Hz, 1H), 7.21 (dt, J=1.5,7.7 Hz, 1H), 5.24 (d, J=4.0 Hz, 1H), 4.16 (s, 3H), 4.04-3.99 (m, 1H),3.80-3.70 (m, 2H), 3.47-3.37 (m, 3H).

Compound 57a:N-(2-Chlorophenyl)-5-(N-((cis)-3-hydroxycyclopentyl)sulfamoyl-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.09, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.46 (d, J=2.0 Hz,1H), 8.39 (d, J=8.0 Hz, 1H), 8.00 (dd, J=2.0, 8.5 Hz, 1H), 7.76 (d,J=7.5 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.41 (t,J=7.8 Hz, 1H), 7.21 (t, J=7.0 Hz, 1H), 4.57 (d, J=4.0 Hz, 1H), 4.15 (s,3H), 3.95-3.86 (m, 1H), 3.46-3.37 (m, 1H), 1.96-1.86 (m, 1H), 1.64-1.37(m, 4H), 1.26-1.16 (m, 1H).

Compound 57b:N-(2-Chlorophenyl)-5-(N-((cis)-3-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.09, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.46 (d, J=2.0 Hz,1H), 8.39 (d, J=8.0 Hz, 1H), 8.00 (dd, J=2.3, 8.8 Hz, 1H), 7.76 (d,J=7.5 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.41 (t,J=7.5 Hz, 1H), 7.21 (t, J=7.0 Hz, 1H), 4.58 (d, J=4.0 Hz, 1H), 4.15 (s,3H), 3.95-3.86 (m, 1H), 3.41-3.37 (m, 1H), 1.96-1.86 (m, 1H), 1.63-1.38(m, 4H), 1.22-1.16 (m, 1H).

Compound 58:N-(2-Chlorophenyl)-2-methoxy-5-(N-(3-methyloxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₅S 410.07, m/z found 411.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.48 (br. s., 1H), 8.45 (d, J=6.2Hz, 2H), 8.38 (d, J=7.7 Hz, 1H), 8.01 (d, J=6.8 Hz, 1H), 7.59 (d, J=7.7Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.42 (t, J=7.4 Hz, 1H), 7.22 (t, J=7.1Hz, 1H), 4.54 (d, J=5.5 Hz, 2H), 4.15 (s, 3H), 4.13 (d, J=6.0 Hz, 2H),1.43 (s, 3H).

Compound 59a:(S)-5-(N-(1-Amino-1-oxopropan-2-ylsulfamoyl)-N-(2-chlorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈ClN₃O₅S 411.07, m/z found 412.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.46 (d, J=1.5 Hz,1H), 8.40 (d, J=8.0 Hz, 1H), 8.03-7.94 (m, 2H), 7.59 (d, J=8.0 Hz, 1H),7.48 (d, J=9.0 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.29 (br. s., 1H), 7.21(t, J=7.3 Hz, 1H), 6.98 (br. s., 1H), 4.15 (s, 3H), 3.71 (quin, J=7.0Hz, 1H), 1.09 (d, J=7.0 Hz, 3H).

Compound 59b:(R)-5-(N-(1-amino-1-oxopropan-2-yl)sulfamoyl)-N-(2-chlorophenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈ClN₃O₅S 411.07, m/z found 412.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.47 (br. s., 1H), 8.46 (br. s.,1H), 8.39 (d, J=8.0 Hz, 1H), 8.05-7.92 (m, 2H), 7.59 (d, J=8.0 Hz, 1H),7.48 (d, J=8.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.29 (br. s., 1H), 7.21(t, J=7.3 Hz, 1H), 6.98 (br. s., 1H), 4.15 (s, 3H), 3.77-3.64 (m, 1H),1.08 (d, J=7.0 Hz, 3H).

Compound 60a:(S*)—N-(2-Chlorophenyl)-5-(N-(1-cyanopropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClN₃O₄S 407.07, m/z found 408.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.47 (d, J=2.2 Hz,1H), 8.38 (d, J=7.8 Hz, 1H), 8.13 (br. s., 1H), 8.03 (dd, J=2.2, 8.8 Hz,1H), 7.59 (d, J=7.8 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.42 (t, J=7.6 Hz,1H), 7.25-7.15 (m, 1H), 4.16 (s, 3H), 3.49-3.39 (m, 1H), 2.75-2.56 (m,2H), 1.00 (d, J=6.6 Hz, 3H).

Compound 60b:(R*)—N-(2-chlorophenyl)-5-(N-(1-cyanopropan-2-yl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClN₃O₄S 407.07, m/z found 408.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.47 (d, J=2.0 Hz,1H), 8.39 (d, J=8.1 Hz, 1H), 8.13 (br. s., 1H), 8.04 (dd, J=2.1, 8.7 Hz,1H), 7.59 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.6 Hz,1H), 7.21 (t, J=7.3 Hz, 1H), 4.16 (s, 3H), 3.50-3.39 (m, 1H), 2.74-2.57(m, 2H), 1.00 (d, J=6.6 Hz, 3H).

Compound 61a:N-(2-Chlorophenyl)-5-(N-((1s,2r)-2-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.09, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.48 (s, 1H), 8.49 (d, J=2.2 Hz, 1H),8.39 (d, J=7.9 Hz, 1H), 8.05 (dd, J=8.8, 2.3 Hz, 1H), 7.57 (d, J=8.0 Hz,1H), 7.46 (d, J=8.8 Hz, 1H), 7.41 (t, J=6.7 Hz, 2H), 7.24-7.15 (m, 1H),4.61 (d, J=4.0 Hz, 1H), 4.14 (s, 3H), 3.80-3.72 (m, 1H), 3.30-3.19 (m,1H), 1.66-1.51 (m, 2H), 1.50-1.23 (m, 4H).

Compound 61b:N-(2-Chlorophenyl)-5-(N-((trans)-2-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.09, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.48 (s, 1H), 8.47 (d, J=2.3 Hz, 1H),8.39 (d, J=7.6 Hz, 1H), 8.01 (dd, J=8.7, 2.4 Hz, 1H), 7.63 (d, J=6.3 Hz,1H), 7.58 (dd, J=8.0, 1.2 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.41 (t,J=7.4 Hz, 1H), 7.20 (td, J=7.8, 1.5 Hz, 1H), 4.68 (d, J=4.3 Hz, 1H),4.15 (s, 3H), 3.83-3.75 (m, 1H), 3.20-3.12 (m, 1H), 1.78-1.61 (m, 2H),1.56-1.45 (m, 2H), 1.40-1.29 (m, 1H), 1.27-1.17 (m, 1H).

Compound 61c:N-(2-chlorophenyl)-5-(N-((trans)-2-hydroxycyclopentyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.09, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d) 10.49 (s, 1H), 8.47 (d, J=2.2 Hz, 1H),8.39 (d, J=8.0 Hz, 1H), 8.01 (dd, J=8.7, 2.3 Hz, 1H), 7.63 (d, J=6.6 Hz,1H), 7.58 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.8 Hz,1H), 7.20 (dd, J=11.1, 4.3 Hz, 1H), 4.68 (d, J=4.3 Hz, 1H), 4.15 (s,3H), 3.81-3.75 (m, 1H), 3.20-3.11 (m, 1H), 1.79-1.61 (m, 2H), 1.56-1.45(m, 2H), 1.40-1.30 (m, 1H), 1.28-1.19 (m, 1H).

Compound 62:N-(2-Chlorophenyl)-2-methoxy-5-(N-(oxetan-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇ClN₂O₅S 396.05, m/z found 397.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.45 (s, 1H), 8.62 (s, 1H), 8.39 (dd,J=17.0, 5.0 Hz, 2H), 7.97 (dd, J=8.8, 2.4 Hz, 1H), 7.57 (dd, J=8.0, 1.1Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.20 (td,J=7.9, 1.5 Hz, 1H), 4.51 (t, J=6.7 Hz, 2H), 4.43-4.33 (m, 1H), 4.27 (t,J=6.3 Hz, 2H), 4.14 (s, 3H).

Compound 63:5-(N-Cyclobutylsulfamoyl)-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₄S 392.12, m/z found 393.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (br. s., 1H), 8.03-7.83 (m,3H), 7.68-7.52 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.13 (t, J=8.8 Hz, 1H),3.96 (s, 3H), 3.64-3.58 (m, 1H), 2.24 (s, 3H), 1.98-1.87 (m, 2H),1.81-1.66 (m, 2H), 1.56-1.44 (m, 2H).

Compound 64:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(thiazol-2-yl)benzamide

LC-MS (ESI): mass calcd. for C₁₅H₁₇N₃O₅S₂ 383.06, m/z found 384.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (br.s, 1H), 8.04 (d, J=2.4 Hz,1H), 7.89-7.97 (m, 2H), 7.55 (d, J=3.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H),7.32 (d, J=3.6 Hz, 1H), 3.98 (s, 3H), 3.66-3.74 (m, 2H), 3.55-3.64 (m,2H), 3.39-3.41 (m, 1H), 1.86-1.96 (m, 1H), 1.57-1.66 (m, 1H).

Compound 65:(S)—N-(2,4-Difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 413.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (br.s, 1H), 8.23 (d, J=2.4 Hz,1H), 7.92-8.00 (m, 3H), 7.35-7.45 (m, 2H), 7.10-7.17 (m, 1H), 3.93 (s,3H), 3.65-3.74 (m, 2H), 3.55-3.64 (m, 2H), 3.35-3.36 (m, 1H) 1.85-1.95(m, 1H), 1.52-1.66 (m, 1H).

Compound 66:(S)—N-(2-Chloro-4-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (br.s, 1H), 8.23 (d, J=2.4 Hz,1H), 7.92-8.00 (m, 3H), 7.35-7.45 (m, 2H), 7.10-7.17 (m, 1H), 4.12 (s,3H), 3.65-3.74 (m, 2H), 3.55-3.64 (m, 2H), 3.35-3.36 (m, 1H) 1.85-1.95(m, 1H), 1.52-1.66 (m, 1H).

Compound 67:(S)—N-(3,5-Difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 413.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-ds) δ 10.57 (br.s, 1H), 7.83-7.89 (m, 3H),7.44 (d, J=7.6 Hz, 2H), 7.36 (d, J=8.8 Hz, 1H), 6.90-7.00 (m, 1H), 3.93(s, 3H), 3.62-3.70 (m, 2H), 3.52-3.61 (m, 2H), 3.30-3.34 (m, 1H),1.82-1.92 (m, 1H), 1.54-1.64 (m, 1H).

Compound 68:(S)—N-(3-Chloro-5-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (br.s, 1H), 8.00 (d, J=2.4 Hz,1H), 7.91-7.97 (m, 2H), 7.68 (s, 1H), 7.60-7.65 (m, 1H), 7.40 (d, J=8.8Hz, 1H), 7.16-7.21 (m, 1H), 3.97 (s, 3H), 3.65-3.73 (m, 2H), 3.56-3.64(m, 2H), 3.30-3.34 (m, 1H), 1.86-1.94 (m, 1H), 1.58-1.66 (m, 1H).

Compound 69:(S)—N-(2,5-Difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 413.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.59 (br.s, 1H), 8.00 (d, J=2.4 Hz,1H), 7.91-7.97 (m, 2H), 7.68 (s, 1H), 7.60-7.65 (m, 1H), 7.40 (d, J=8.8Hz, 1H), 7.16-7.21 (m, 1H), 3.97 (s, 3H), 3.65-3.73 (m, 2H), 3.56-3.64(m, 2H), 3.30-3.34 (m, 1H), 1.86-1.94 (m, 1H), 1.58-1.66 (m, 1H).

Compound 70:(S)—N-(2-Chloro-5-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.61 (br.s, 1H), 8.48 (d, J=2.0 Hz,1H), 8.32 (dd, J=11.2 Hz, J=2.4 Hz, 1H), 7.97-8.07 (m, 2H), 7.65 (dd,J=8.8 Hz, J=6.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.04-7.14 (m, 1H), 4.17(s, 3H), 3.66-3.74 (m, 2H), 3.55-3.65 (m, 2H), 3.33-3.35 (m, 1H),1.85-1.95 (m, 1H), 1.56-1.66 (m, 1H).

Compound 71:(S)—N-(2,5-Dichlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈Cl₂N₂O₅S 444.03, m/z found 445.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.58 (br.s, 1H), 8.50 (d, J=2.0 Hz,1H), 8.46 (d, J=2.0 Hz, 1H), 7.98-8.10 (m, 2H), 7.64 (d, J=8.4 Hz, 1H),7.52 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 4.16 (s, 3H),3.66-3.74 (m, 2H), 3.54-3.65 (m, 2H), 3.33-3.36 (m, 1H), 1.85-1.96 (m,1H), 1.56-1.67 (m, 1H).

Compound 72:(S)—N-(3,4-Dichlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈Cl₂N₂O₅S 444.03, m/z found 445.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.53 (br.s, 1H), 8.10 (d, J=2.0 Hz,1H), 8.00 (d, J=2.4 Hz, 1H), 7.88-7.97 (m, 2H), 7.58-7.71 (m, 2H), 7.40(d, J=8.8 Hz, 1H), 3.97 (s, 3H), 3.65-3.74 (m, 2H), 3.55-3.64 (m, 2H),3.36-3.39 (m, 1H), 1.86-1.96 (m, 1H), 1.57-1.67 (m, 1H).

Compound 73:(S)—N-(4-Cyano-2-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈FN₃O₅S 419.10, m/z found 420.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.53 (br. s., 1H), 8.43 (t, J=7.9Hz, 1H), 8.27 (s, 1H), 8.00 (d, J=10.5 Hz, 3H), 7.76 (d, J=8.0 Hz, 1H),7.47 (d, J=8.8 Hz, 1H), 4.07 (s, 3H), 3.74-3.53 (m, 4H), 3.39-3.36 (m,1H), 1.96-1.85 (m, 1H), 1.67-1.57 (m, 1H).

Compound 74:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(2,4,5-trifluorophenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇F₃N₂O₅S 430.08, m/z found 431.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (br. s, 1H), 8.24 (d, J=2.3Hz, 1H), 8.16 (td, J=8.1, 12.0 Hz, 1H), 8.01-7.94 (m, 2H), 7.74 (m, 1H),7.45 (d, J=9.0 Hz, 1H), 4.05 (s, 3H), 3.74-3.65 (m, 2H), 3.64-3.54 (m,2H), 3.38-3.34 (m, 1H), 1.96-1.85 (m, 1H), 1.67-1.57 (m, 1H).

Compound 75:(S)—N-(5-Chloro-2,4-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇ClF₂N₂O₅S 446.05, m/z found 447.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.24 (br. s, 1H), 8.28-8.20 (m,2H), 8.01-7.93 (m, 2H), 7.72 (t, J=9.9 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H),4.04 (s, 3H), 3.73-3.65 (m, 2H), 3.64-3.55 (m, 2H), 3.38-3.34 (m, 1H),1.95-1.85 (m, 1H), 1.64-1.59 (m, 1H).

Compound 76:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(2,4,6-trifluorophenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇F₃N₂O₅S 430.08, m/z found 431.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 9.86 (br., s, 1H), 8.18 (d, J=2.5Hz, 1H), 8.00-7.91 (m, 2H), 7.42 (d, J=8.8 Hz, 1H), 7.34 (t, J=8.5 Hz,2H), 4.01 (s, 3H), 3.73-3.56 (m, 4H), 3.37 (s, 1H), 1.96-1.84 (m, 1H),1.66-1.57 (m, 1H).

Compound 77:(S)—N-(3-Chloro-2,4-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇ClF₂N₂O₅S 446.05, m/z found 447.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.22 (d, J=2.0 Hz,1H), 8.02-7.86 (m, 3H), 7.49-7.33 (m, 2H), 4.04 (s, 3H), 3.75-3.53 (m,4H), 3.39-3.35 (m, 1H), 1.95-1.85 (m, 1H), 1.67-1.57 (m, 1H).

Compound 78:(S)—N-(2-Chloro-4,6-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇ClF₂N₂O₅S 446.05, m/z found 447.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d6) δ 9.94 (br. s., 1H), 8.19 (d, J=2.5Hz, 1H), 7.98 (dd, J=2.4, 8.7 Hz, 2H), 7.57-7.46 (m, 2H), 7.43 (d, J=9.0Hz, 1H), 4.03 (s, 3H), 3.74-3.54 (m, 4H), 3.39-3.36 (m, 1H), 1.96-1.85(m, 1H), 1.67-1.58 (m, 1H).

Compound 79:(S)-2-Methoxy-N-(1-methyl-1H-pyrazol-3-yl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₆H₂₀N₄O₅S 380.12, m/z found 381.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d) δ 10.45 (s, 1H), 8.09 (d, J=2.5 Hz, 1H),7.95-7.88 (m, 2H), 7.62 (d, J=2.2 Hz, 1H), 7.38 (d, J=8.9 Hz, 1H), 6.58(d, J=2.2 Hz, 1H), 3.99 (s, 3H), 3.77 (s, 3H), 3.71-3.55 (m, 4H),3.35-3.31 (m, 1H), 1.93-1.86 (m, 1H), 1.65-1.58 (m, 1H).

Compound 80:(S)—N-(4-cyano-2,6-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₇F₂N₃O₅S 437.09, m/z found 438.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.25 (s, 1H), 8.16 (d, J=1.5 Hz, 1H),8.00 (dd, J=2.4, 8.8 Hz, 1H), 7.93 (m, 3H), 7.43 (d, J=8.8 Hz, 1H), 4.01(s, 3H), 3.74-3.60 (m, 4H), 3.39-3.33 (m, 1H), 1.97-1.86 (m, 1H),1.67-1.57 (m, 1H).

Compound 81:(S)—N-(2,6-Dichlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈Cl₂N₂O₅S 444.03, m/z found 445.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (br.s, 1H), 8.18 (d, J=2.8 Hz,1H), 7.97 (dd, J=2.4 Hz, J=8.8 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H),7.45-7.35 (m, 2H), 4.02 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 82:(S)-2-methoxy-N-(4-methylthiazol-2-yl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₆H₁₉N₃O₅S₂ 397.47, m/z found 398.0[M+H]⁺, reverse phase ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.05(d, J=2.0 Hz, 1H), 7.89-7.98 (m, 2H), 7.40 (d, J=8.8 Hz, 1H), 6.85 (s,1H), 3.98 (s, 3H), 3.65-3.74 (m, 2H), 3.54-3.64 (m, 2H), 3.35-3.38 (m,1H), 2.29 (s, 3H), 1.85-1.96 (m, 1H), 1.57-1.67 (m, 1H).

Compound 83:(S)—N-(4,5-dimethylthiazol-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): R_(T)=4.12 min, mass calcd. for C₁₇H₂₁N₃O₅S₂ 411.50, m/zfound 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.04 (d,J=2.4 Hz, 1H), 7.88-7.98 (m, 2H), 7.39 (d, J=8.8 Hz, 1H), 3.98 (s, 3H),3.65-3.73 (m, 2H), 3.54-3.64 (m, 2H), 3.35-3.38 (m, 1H), 2.28 (s, 3H),2.19 (s, 3H), 1.85-1.97 (m, 1H), 1.57-1.66 (m, 1H).

Compound 84:(S)-2-methoxy-N-(5-methylthiazol-2-yl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): R^(T)=3.95 min, mass calcd. for C₁₆H₁₉N₃O₅S₂ 397.47, m/zfound 398.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.04 (d,J=2.4 Hz, 1H), 7.89-7.98 (m, 2H), 7.40 (d, J=8.8 Hz, 1H), 7.21 (s, 1H),3.98 (s, 3H), 3.65-3.73 (m, 2H), 3.55-3.64 (m, 2H), 3.35-3.38 (m, 1H),2.39 (s, 3H), 1.85-1.95 (m, 1H), 1.57-1.67 (m, 1H).

Compound 85:(S)—N-(2,4-Dichlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈Cl₂N₂O₅S 444.03, m/z found 445.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (br.s, 1H), 8.44 (d, J=2.4 Hz,1H), 8.39 (d, J=8.8 Hz, 1H), 8.05-7.95 (m, 2H), 7.77 (d, J=2.4 Hz, 1H),7.50 (dd, J=2.0 Hz, J=9.2 Hz, 2H), 4.15 (s, 3H), 3.74-3.54 (m, 4H),3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 86:(S)—N-(3,5-Dichlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈Cl₂N₂O₅S 444.03, m/z found 445.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (br.s, 1H), 8.00 (d, J=2.4 Hz,1H), 7.98-7.90 (m, 2H), 7.82 (d, J=1.6 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H),7.36 (t, J=1.6 Hz, 1H), 3.98 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m,1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 87:(S)—N-(3-Cyano-5-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈FN₃O₃S 419.10, m/z found 420.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (br.s, 1H), 8.10-7.90 (m, 5H),7.62 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 3.98 (s, 3H), 3.74-3.54(m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 88:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(2,3,4-trifluorophenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇F₃N₂O₅S 430.08, m/z found 431.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (br.s, 1H), 8.20 (d, J=2.4 Hz,1H), 8.02-7.92 (m, 2H), 7.80-7.70 (m, 1H), 7.43 (d, J=8.8 Hz, 1H),7.42-7.32 (m, 1H), 4.04 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 89:(S)—N-(3-Chloro-4-cyanophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈ClN₃O₅S 435.07, m/z found 436.0[M+H]⁺. ¹H NMR (400 Hz, DMSO-d₆) δ 10.83 (br.s, 1H), 8.15 (d, J=2.0 Hz,1H), 8.02-7.88 (m, 4H), 7.80 (dd, J=2.0 Hz, J=8.4 Hz, 1H), 7.41 (d,J=8.8 Hz, 1H), 3.97 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 90:(S)—N-(4-Cyano-3-fluorophenyl-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈FN₃O₅S 419.10, m/z found 420.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (br.s, 1H), 8.02-7.84 (m, 5H),7.63 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 3.74-3.54(m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 91:(S)—N-(4-Chloro-2,6-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇ClF₂N₂O₅S 446.05, m/z found 447.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (br.s, 1H), 8.17 (d, J=2.4 Hz,1H), 8.02-7.92 (m, 2H), 7.52 (d, J=7.6 Hz, 2H), 7.42 (d, J=9.2 Hz, 1H),4.01 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H),1.68-1.56 (m, 1H).

Compound 92:(S)—N-(3-Cyano-2-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈FN₃O₅S 419.10, m/z found 420.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (br.s, 1H), 8.35 (t, J=7.6 Hz,1H), 8.23 (d, J=2.0 Hz, 1H), 8.10-7.94 (m, 2H), 7.80-7.70 (m, 1H),7.50-7.40 (m, 2H), 4.06 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 93:(S)—N-(3-Chloro-2,6-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇ClF₂N₂O₅S 446.05, m/z found 447.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (br.s, 1H), 8.18 (d, J=2.4 Hz,1H), 8.05-7.90 (m, 2H), 7.70-7.60 (m, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.32(t, J=8.4 Hz, 1H), 4.02 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 94:(S)—N-(3-Chloro-5-cyanophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈ClN₃O₅S 435.07, m/z found 436.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (br.s, 1H), 8.16 (t, J=2.0 Hz,1H), 8.11 (t, J=1.6 Hz, 1H), 8.03 (d, J=2.4 Hz, 1H), 8.00-7.90 (m, 2H),7.79 (dd, J=1.2 Hz, J=2.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 3.98 (s, 3H),3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m,1H).

Compound 95:(S)—N-(3-Cyano-4-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈FN₃O₅S 419.10, m/z found 420.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (br.s, 1H), 8.26-8.20 (m, 1H),8.08-8.00 (m, 2H), 8.00-7.90 (m, 2H), 7.56 (t, J=9.2 Hz, 1H), 7.40 (d,J=8.8 Hz, 1H), 3.98 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 96:(S)—N-(2-Chloro-3,5-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇ClF₂N₂O₅S 446.05, m/z found 447.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (br.s, 1H), 8.45 (d, J=2.8 Hz,1H), 8.19 (d, J=10.8 Hz, 1H), 8.06-8.00 (m, 2H), 7.52 (d, J=9.2 Hz, 1H),7.40-7.30 (m, 1H), 4.17 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.56 (m, 1H).

Compound 97:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(3,4,5-trifluorophenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇F₃N₂O₅S 430.08, m/z found 431.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (br.s, 1H), 8.02-7.88 (m, 3H),7.66 (dd, J=6.4 Hz, J=10.4 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H), 3.97 (s,3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56(m, 1H).

Compound 98:(S)—N-(4-Cyano-2,5-difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₇F₂N₃O₅S 437.09, m/z found 438.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (br.s, 1H), 8.41 (dd, J=6.0Hz, J=11.2 Hz, 1H), 8.25 (d, J=2.8 Hz, 1H), 8.13 (dd, J=6.0 Hz, J=10.8Hz, 1H), 8.05-7.95 (m, 2H), 7.47 (d, J=9.2 Hz, 1H), 4.06 (s, 3H),3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m,1H).

Compound 99:(S)—N-(2-Fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₅S 394.10, m/z found 395.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (s, 1H), 8.28 (d, J=2.4 Hz,1H), 8.15-8.06 (m, 1H), 8.12-7.90 (m, 2H), 7.45 (d, J=8.8 Hz, 1H),7.38-7.30 (m, 1H), 7.28-7.17 (m, 2H), 4.07 (s, 3H), 3.75-3.66 (m, 2H),3.65-3.54 (m, 2H), 3.42-3.38 (m, 1H), 1.97-1.84 (m, 1H), 1.68-1.55 (m,1H).

Compound 100:(S)—N-(3-Fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₅S 394.10, m/z found 395.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 7.99 (d, J=2.4 Hz,1H), 7.96-7.89 (m, 2H), 7.75-7.68 (m, 1H), 7.47 (d, J=8.7 Hz, 1H),7.43-7.36 (m, 2H), 6.98-6.93 (m, 1H), 3.97 (s, 3H), 3.75-3.64 (m, 2H),3.63-3.55 (m, 2H), 3.39-3.36 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.55 (m,1H).

Compound 101:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(4-(trifluoromethyl)phenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₅S 444.10, m/z found 444.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.02-7.86 (m, 5H),7.77-7.70 (m, 2H), 7.40 (d, J=8.8 Hz, 1H), 3.97 (s, 3H), 3.74-3.66 (m,2H), 3.64-3.55 (m, 2H), 3.41-3.38 (m, 1H), 1.96-1.86 (m, 1H), 1.68-1.58(m, 1H).

Compound 102:(S)—N-(3-cyanophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉N₃O₅S 401.10, m/z found 402.0 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.21 (s, 1H), 8.02 (d, J=2.4Hz, 1H), 8.01-7.89 (m, 3H), 7.59-7.57 (m, 2H), 7.40 (d, J=8.9 Hz, 1H),3.98 (s, 3H), 3.74-3.67 (m, 2H), 3.65-3.57 (m, 2H), 3.37 (dd, J=8.7, 4.2Hz, 1H), 1.97-1.86 (m, 1H), 1.68-1.61 (m, 1H).

Compound 103:(S)—N-(2-Chloro-6-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.20 (d, J=2.4 Hz,1H), 8.01-7.96 (m, 2H), 7.49-7.30 (m, 4H), 4.03 (s, 3H), 3.73-3.66 (m,2H), 3.65-3.54 (m, 2H), 3.40-3.37 (m, 1H), 1.96-1.87 (m, 1H), 1.68-1.57(m, 1H).

Compound 104:(S)—N-(4-Cyanophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉N₃O₅S 401.10, m/z found 401.9 [M+H]⁺.¹H NMR (400 MHz, DMSO-d) δ 10.68 (s, 1H), 8.01-7.88 (m, 5H), 7.85-7.81(m, 2H), 7.40 (d, J=8.8 Hz, 1H), 3.97 (s, 3H), 3.74-3.67 (m, 2H),3.66-3.55 (m, 2H), 3.38-3.35 (m, 1H), 1.97-1.86 (m, 1H), 1.67-1.58 (m,1H).

Compound 105:(S)—N-(2,6-Difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 413.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 8.18 (d, J=2.4 Hz,1H), 8.01-7.91 (m, 2H), 7.47-7.36 (m, 2H), 7.27-7.15 (m, 2H), 4.02 (s,3H), 3.73-3.65 (m, 2H), 3.64-3.54 (m, 2H), 3.38-3.35 (m, 1H), 1.95-1.85(m, 1H), 1.66-1.56 (m, 1H).

Compound 106:(S)—N-(4-(Difluoromethoxy)phenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀F₂N₂O₆S 442.10, m/z found 443.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.34 (br.s, 1H), 8.00 (d, J=2.2 Hz,1H), 7.95-7.90 (m, 2H), 7.78-7.73 (m, 2H), 7.41-7.35 (m, 1H), 7.21-7.16(m, 3H), 3.97 (s, 3H), 3.73-3.66 (m, 2H), 3.64-3.56 (m, 2H), 3.50-3.44(m, 1H), 1.96-1.87 (m, 1H), 1.66-1.58 (m, 1H).

Compound 107:(S)—N-(3-(Difluoromethoxy)phenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀F₂N₂O₆S 442.10, m/z found 442.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (br.s, 1H), 7.98 (d, J=2.4 Hz,1H), 7.96-7.87 (m, 2H), 7.73-7.67 (m, 1H), 7.53 (d, J=8.3 Hz, 1H),7.43-7.37 (m, 2H), 7.23 (s, 1H), 6.93 (dd, J=2.0, 8.1 Hz, 1H), 3.97 (s,3H), 3.70-3.57 (m, 4H), 3.39-3.38 (m, 1H), 1.94-1.86 (m, 1H), 1.66-1.59(m, 1H).

Compound 108:(S)—N-(4-Chlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₅S 410.07, m/z found 411.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (br.s, 1H), 7.99 (d, J=2.4 Hz,1H), 7.95-7.89 (m, 2H), 7.79-7.73 (m, 2H), 7.44-7.36 (m, 3H), 3.96 (s,3H), 3.73-3.66 (m, 2H), 3.62-3.55 (m, 2H), 3.38-3.38 (m, 1H), 1.95-1.85(m, 1H), 1.66-1.59 (m, 1H).

Compound 109:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(3-(trifluoromethyl)phenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₅S 444.10, m/z found 445.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d) δ 10.58 (br. s., 1H), 8.21 (s, 1H),8.01 (d, J=2.2 Hz, 1H), 7.97-7.87 (m, 3H), 7.61 (t, J=7.9 Hz, 1H), 7.48(d, J=7.6 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 3.97 (s, 3H), 3.72-3.66 (m,2H), 3.63-3.57 (m, 2H), 3.41 (br. s., 1H), 1.96-1.88 (m, 1H), 1.67-1.59(m, 1H).

Compound 110:(S)-2-Methoxy-N-(1-methyl-1H-indazol-4-yl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₂N₄O₅S 430.13, m/z found 431.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 8.21 (s, 1H), 8.12 (d, J=2.0Hz, 1H), 7.99-7.90 (m, 2H), 7.84 (d, J=4.5 Hz, 1H), 7.46-7.34 (m, 3H),4.04 (s, 3H), 4.04 (s, 3H), 3.74-3.66 (m, 2H), 3.66-3.55 (m, 2H),3.42-3.39 (m, 1H), 1.98-1.85 (m, 1H), 1.70-1.59 (m, 1H).

Compound 111:(S)—N-(3,4-Difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 413.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.00 (d, J=2.5 Hz,1H), 7.96-7.86 (m, 3H), 7.51-7.42 (m, 2H), 7.39 (d, J=9.0 Hz, 1H), 3.97(s, 3H), 3.74-3.65 (m, 2H), 3.65-3.55 (m, 2H), 3.42-3.39 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.57 (m, 1H).

Compound 112:(S)—N-(3-Chloro-4-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.04 (dd, J=2.5, 7.0Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.97-7.89 (m, 2H), 7.70-7.62 (m, 1H),7.47-7.36 (m, 2H), 3.97 (s, 3H), 3.74-3.65 (m, 2H), 3.65-3.55 (m, 2H),3.36-3.34 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 113:(S)—N-(2,3-Difluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 429.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.23 (d, J=2.0 Hz,1H), 8.03-7.91 (m, 2H), 7.87-7.77 (m, 1H), 7.44 (d, J=8.5 Hz, 1H),7.32-7.20 (m, 2H), 4.05 (s, 3H), 3.74-3.65 (m, 2H), 3.64-3.54 (m, 2H),3.42-3.39 (m, 1H), 1.95-1.85 (m, 1H), 1.67-1.57 (m, 1H).

Compound 114:(S)—N-(4-Chloro-2-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (s, 1H), 8.25 (d, J=2.5 Hz,1H), 8.10 (t, J=8.8 Hz, 1H), 8.01-7.87 (m, 2H), 7.58 (dd, J=2.0, 10.5Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 4.05 (s, 3H),3.74-3.64 (m, 2H), 3.64-3.54 (m, 2H), 3.35-3.33 (m, 1H), 1.95-1.84 (m,1H), 1.67-1.57 (m, 1H).

Compound 115:(S)—N-(4-Chloro-3-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 428.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 7.99 (d, J=2.5 Hz,1H), 7.97-7.86 (m, 3H), 7.60-7.54 (m, 1H), 7.54-7.49 (m, 1H), 7.39 (d,J=8.5 Hz, 1H), 3.96 (s, 3H), 3.74-3.64 (m, 2H), 3.64-3.55 (m, 2H),3.36-3.34 (m, 1H), 1.96-1.85 (m, 1H), 1.67-1.57 (m, 1H).

Compound 116:(S)—N-(5-Fluoropyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈FN₃O₅S 395.10, m/z found 396.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (br.s, 1H), 8.39 (d, J=3.2 Hz,1H), 8.28 (dd, J=4.0, 9.2 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 8.00-7.90 (m,2H), 7.83 (td, J=3.2, 8.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 4.03 (s, 3H),3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.56 (m,1H).

Compound 117:(S)—N-(5-Fluoropyrimidin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₆H₁₇FN₄O₅S 396.09, m/z found 397.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (br.s, 1H), 8.77 (s, 2H), 7.98(d, J=2.4 Hz, 1H), 7.92 (dd, J=2.4, 8.4 Hz, 2H), 7.34 (d, J=8.8 Hz, 1H),3.90 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H),1.68-1.56 (m, 1H).

Compound 118:(S)—N-(3,5-Difluoropyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇F₂N₃O₅S 413.09, m/z found 414.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (brs, 1H), 8.40 (d, J=2.0 Hz,1H), 8.17-8.05 (m, 2H), 8.00-7.91 (m, 2H), 7.40 (d, J=8.0, 1H), 3.98 (s,3H), 3.74-3.55 (m, 4H), 3.40-3.30 (m, 1H), 1.96-1.85 (m, 1H), 1.67-1.57(m, 1H).

Compound 119:((S)—N-(3-Chloro-5-fluoropyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇ClFN₃O₅S 429.06, m/z found 430.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (br. s., 1H), 8.50 (d, J=2.5Hz, 1H), 8.25 (dd, J=2.5, 8.0 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.96 (dd,J=2.3, 8.8 Hz, 2H), 7.40 (d, J=8.5 Hz, 1H), 4.00 (s, 3H), 3.74-3.54 (m,4H), 3.39-3.35 (m, 1H), 1.96-1.85 (m, 1H), 1.62 (dt, J=6.3, 12.4 Hz,1H).

Compound 120:(S)—N-(5-Chloro-3-fluoropyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₇ClFN₃O₅S 429.06, m/z found 430.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (br. s., 1H), 8.42-8.36 (m,1H), 8.21 (d, J=9.5 Hz, 1H), 8.10 (br. s., 1H), 8.00-7.89 (m, 2H), 7.39(d, J=9.0 Hz, 1H), 3.97 (br. s., 3H), 3.73-3.56 (m, 4H), 3.37 (br. s.,1H), 1.89 (d, J=5.5 Hz, 1H), 1.62 (d, J=6.0 Hz, 1H).

Compound 121:(S)—N-(3-Chloropyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈ClN₃O₅S 411.07, m/z found 412.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 8.41 (dd, J=1.4, 4.8Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 8.06 (dd, J=1.4, 8.0 Hz, 1H), 7.96 (dd,J=2.4, 8.8 Hz, 2H), 7.43-7.32 (m, 2H), 4.00 (s, 3H), 3.73-3.55 (m, 4H),3.39-3.35 (m, 1H), 1.95-1.84 (m, 1H), 1.62 (dt, J=5.4, 12.4 Hz, 1H).

Compound 122:(S)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₅S 394.10, m/z found 395.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (brs, 1H), 8.00 (d, J=2.3 Hz,1H), 7.96-7.88 (m, 2H), 7.80-7.71 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.20(t, J=8.9 Hz, 2H), 3.97 (s, 3H), 3.74-3.54 (m, 4H), 3.39-3.35 (m, 1H),1.97-1.84 (m, 1H), 1.68-1.58 (m, 1H).

Compound 123:(S)—N-(2-Bromophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉BrN₂O₅S 454.02, m/z found 454.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.48 (d, J=2.4 Hz,1H), 8.37 (d, J=8.0 Hz, 1H), 8.02 (dd, J=2.4, 8.8 Hz, 1H), 7.73 (dd,J=1.4, 8.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.14(dt, J=1.4, 7.8 Hz, 1H), 4.18 (s, 3H), 3.73-3.55 (m, 4H), 3.38-3.36 (m,1H), 1.97-1.82 (m, 1H), 1.68-1.56 (m, 1H).

Compound 124:(S)—N-(3-Bromophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉BrN₂O₅S 454.02, m/z found 455.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 8.08-8.04 (m, 1H),7.99 (d, J=2.4 Hz, 1H), 7.95-7.88 (m, 2H), 7.67 (td, J=2.4, 6.8 Hz, 1H),7.39 (d, J=8.4 Hz, 1H), 7.35-7.28 (m, 2H), 3.97 (s, 3H), 3.74-3.65 (m,2H), 3.64-3.55 (m, 2H), 3.40-3.34 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.58(m, 1H).

Compound 125:(S)—N-(4-Bromophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉BrN₂O₅S 454.02, m/z found 455.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.02-7.97 (m, 1H),7.95-7.88 (m, 2H), 7.74-7.67 (m, 2H), 7.57-7.51 (m, 2H), 7.38 (d, J=9.0Hz, 1H), 3.96 (s, 3H), 3.74-3.54 (m, 4H), 3.40-3.34 (m, 1H), 1.96-1.85(m, 1H), 1.68-1.58 (m, 1H).

Compound 126:(S)—N-(3-Chlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₅S 410.07, m/z found 410.9[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (br.s, 1H), 7.99 (d, J=2.2 Hz,1H), 7.96-7.87 (m, 3H), 7.62 (d, J=8.3 Hz, 1H), 7.42-7.35 (m, 2H),7.21-7.16 (m, 1H), 3.97 (s, 3H), 3.74-3.55 (m, 4H), 3.41-3.35 (m, 1H),1.96-1.86 (m, 1H), 1.68-1.61 (m, 1H).

Compound 127:(S)—N-(2-Chlorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₅S 410.07, m/z found 411.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.45 (d, J=2.5 Hz,1H), 8.37 (d, J=7.3 Hz, 1H), 8.01 (dd, J=2.5, 8.8 Hz, 2H), 7.59 (dd,J=1.4, 8.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.21(dt, J=1.6, 7.7 Hz, 1H), 4.15 (s, 3H), 3.73-3.65 (m, 2H), 3.64-3.54 (m,2H), 3.33-3.30 (m, 1H), 1.97-1.87 (m, 1H), 1.66-1.57 (m, 1H).

Compound 128:(S)—N-(2-(Difluoromethoxy)phenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀F₂N₂O₆S 442.10, m/z found 443.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d) δ 10.44 (s, 1H), 8.50-8.44 (m, 2H),8.04-7.97 (m, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.35-7.29 (m,2H), 7.25-7.19 (m, 1H), 7.18 (s, 0.25H), 4.14 (s, 3H), 3.73-3.64 (m,2H), 3.64-3.54 (m, 2H), 3.39-3.35 (m, 1H), 1.95-1.84 (m, 1H), 1.66-1.57(m, 1H).

Compound 129:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(p-tolyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂N₂O₅S 390.12, m/z found 391.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), 8.01 (d, J=2.5 Hz, 1H),7.94-7.88 (m, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.37 (d, J=9.0 Hz, 1H), 7.16(d, J=8.3 Hz, 2H), 3.97 (s, 3H), 3.73-3.55 (m, 4H), 3.39-3.35 (m, 1H),2.28 (s, 3H), 1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 130:(S)—N-(2-Fluoro-6-methoxyphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₆S 424.11, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 8.22 (d, J=2.0 Hz,1H), 7.99-7.91 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.35-7.27 (m, 1H),6.98-6.86 (m, 2H), 4.03 (s, 3H), 3.83 (s, 3H), 3.73-3.66 (m, 2H),3.64-3.55 (m, 2H), 3.39-3.32 (m, 1H), 1.96-1.84 (m, 1H), 1.67-1.56 (m,1H).

Compound 131:(S)—N-(4-Fluoro-2-methylphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 8.24 (d, J=2.3 Hz,1H), 7.98-7.91 (m, 2H), 7.73 (dd, J=5.5, 8.8 Hz, 1H), 7.43 (d, J=9.0 Hz,1H), 7.16 (dd, J=2.9, 9.7 Hz, 1H), 7.07 (dt, J=3.0, 8.7 Hz, 1H), 4.05(s, 3H), 3.73-3.65 (m, 2H), 3.64-3.55 (m, 2H), 3.39-3.35 (m, 1H), 2.31(s, 3H), 1.96-1.86 (m, 1H), 1.67-1.58 (m, 1H).

Compound 132:(S)—N-(5-fluoro-3-methylpyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₅S 409.11, m/z found 410.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (br.s, 1H), 8.27 (s, 1H), 8.08(s, 1H), 7.93 (dd, J=8.8, 2.3 Hz, 1H), 7.75 (dd, J=9.0, 2.8 Hz, 1H),7.37 (d, J=8.5 Hz, 1H), 3.97 (s, 3H), 3.76-3.51 (m, 5H), 2.28 (s, 3H),1.96-1.82 (m, 1H), 1.68-1.54 (m, 1H).

Compound 133:(S)-2-Methoxy-N-(3-methylpyridin-2-yl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₁N₃O₅S 391.12, m/z found 392.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (br.s, 1H), 8.26 (s, 1H), 8.09 (s,1H), 7.93 (dd, J=2.0, 8.8 Hz, 1H), 7.73 (d, J=7.3 Hz, 1H), 7.36 (d,J=8.6 Hz, 1H), 7.30-7.16 (m, 1H), 3.96 (s, 3H), 3.75-3.53 (m, 5H), 2.26(s, 3H), 1.96-1.84 (m, 1H), 1.68-1.55 (m, 1H).

Compound 134:(S)—N-(3-fluoro-2-methoxyphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₆S 424.11, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.52 (d, J=2.5 Hz,1H), 8.29 (dd, J=10.8, 3.1 Hz, 1H), 8.07-7.95 (m, 2H), 7.51 (d, J=8.9Hz, 1H), 7.12 (dd, J=9.1, 5.1 Hz, 1H), 6.94 (td, J=8.6, 3.2 Hz, 1H),4.17 (s, 3H), 3.96 (s, 3H), 3.75-3.52 (m, 4H), 3.40-3.35 (m, 1H),1.96-1.83 (m, 1H), 1.65-1.55 (m, 1H).

Compound 135:(S)—N-(4-fluoro-2-methoxyphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁FN₂O₆S 424.11, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.49 (d, J=2.4 Hz,1H), 8.43-8.32 (m, 1H), 8.06-7.90 (m, 2H), 7.49 (d, J=8.8 Hz, 1H), 7.07(dd, J=10.7, 2.7 Hz, 1H), 6.82 (td, J=8.7, 2.7 Hz, 1H), 4.15 (s, 3H),3.97 (s, 3H), 3.74-3.64 (m, 2H), 3.64-3.53 (m, 2H), 3.33-3.26 (m, 1H),1.95-1.82 (m, 1H), 1.67-1.54 (m, 1H).

Compound 136:(S)—N-(2-ethoxyphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₄N₂O₆S 420.14, m/z found 421.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.48(d, J=7.6 Hz, 1H), 8.05-7.95 (m, 2H), 7.50 (d, J=8.9 Hz, 1H), 7.15-7.04(m, 2H), 7.00-6.90 (m, 1H), 4.23-4.17 (m, 2H), 4.16 (s, 3H), 3.73-3.64(m, 2H), 3.64-3.53 (m, 2H), 3.33-3.30 (m, 1H), 1.93-1.83 (m, 1H),1.65-1.57 (m, 1H), 1.47 (t, J=7.0 Hz, 3H).

Compound 137a:N-(2-chloro-5-methylphenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.1, m/z found 425.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (br. s., 1H), 8.41 (br. s,1H), 8.22 (br. s, 1H), 8.08-7.83 (m, 2H), 7.47 (dd, J=8.4, 15.0 Hz, 2H),7.13-6.93 (m, J=7.8 Hz, 1H), 4.96 (s, 1H), 4.14 (br. s., 3H), 3.84-3.64(m, 1H), 3.55-3.43 (m, 1H), 2.34 (br. s., 3H), 2.13-1.75 (m, 4H).

Compound 137b:N-(2-Chloro-5-methylphenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.1, m/z found 425.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.42 (s, 1H), 8.22(s, 1H), 8.02-7.85 (m, 2H), 7.53-7.40 (m, 2H), 7.03 (dd, J=1.5, 8.1 Hz,1H), 5.02 (d, J=5.6 Hz, 1H), 4.21-4.08 (m, 3H), 3.72-3.61 (m, 1H),3.16-3.05 (m, 1H), 2.34 (s, 3H), 2.30-2.19 (m, 2H), 1.64-1.52 (m, 2H).

Compound 138a:N-(2-Chloro-6-methylphenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.1, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.09 (br. s., 1H),7.89 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.33-7.23 (m, 2H), 4.96(d, J=3.9 Hz, 1H), 4.13 (m, 1H), 4.01 (s, 3H), 3.73 (m, 1H), 2.35-2.22(m, 3H), 2.04-1.85 (m, 4H).

Compound 138b:N-(2-Chloro-6-methylphenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.1, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ9.87 (s, 1H), 8.11 (d, J=2.5 Hz, 1H),7.93-7.85 (m, 2H), 7.43-7.35 (m, 2H), 7.32-7.23 (m, 2H), 5.03 (d, J=6.0Hz, 1H), 4.01 (s, 3H), 3.74-3.59 (m, 1H), 3.17-3.04 (m, 1H), 2.30-2.18(m, 5H), 1.65-1.52 (m, 2H).

Compound 139a:N-(2-Chloro-3-methoxyphenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₆S 440.1, m/z found 441.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.43 (d, J=1.7 Hz,1H), 8.05 (d, J=8.1 Hz, 1H), 7.96 (dd, J=2.1, 8.7 Hz, 2H), 7.49 (d,J=8.8 Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 4.95 (d,J=4.9 Hz, 1H), 4.20-4.07 (m, 4H), 3.90 (s, 3H), 3.73 (br. s., 1H),2.01-1.84 (m, 4H).

Compound 139b:N-(2-Chloro-3-methoxyphenyl)-5-(N-((cis-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybe

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₆S 440.1, m/z found 441.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d) δ 10.52 (s, 1H), 8.44 (d, J=2.0 Hz,1H), 8.05 (d, J=8.5 Hz, 1H), 8.00-7.89 (m, 2H), 7.49 (d, J=8.5 Hz, 1H),7.36 (t, J=8.3 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 5.02 (d, J=5.5 Hz, 1H),4.16 (s, 3H), 3.90 (s, 3H), 3.73-3.60 (m, 1H), 3.16-3.04 (m, 1H),2.28-2.17 (m, 2H), 1.63-1.51 (m, 2H).

Compound 140a:N-(2-Chloro-3-methylphenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.1, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ10.51 (s, 1H), 8.45-8.39 (m, 1H),8.24 (d, J=8.0 Hz, 1H), 8.02-7.91 (m, 2H), 7.49 (d, J=9.0 Hz, 1H),7.34-7.27 (m, 1H), 7.22-7.15 (m, 1H), 4.98 (d, J=5.0 Hz, 1H), 4.19-4.08(m, 4H), 3.78-3.68 (m, 1H), 2.40 (s, 3H), 2.04-1.83 (m, 4H).

Compound 140b:N-(2-Chloro-3-methylphenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₁ClN₂O₅S 424.1, m/z found 425.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.43 (d, J=2.5 Hz,1H), 8.25 (d, J=8.0 Hz, 1H), 8.00-7.87 (m, 2H), 7.48 (d, J=9.0 Hz, 1H),7.35-7.26 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 5.03 (d, J=5.5 Hz, 1H), 4.15(s, 3H), 3.73-3.60 (m, 1H), 3.18-3.01 (m, 1H), 2.40 (s, 3H), 2.29-2.17(m, 2H), 1.62-1.50 (m, 2H).

Compound 141:(cis-N-(5-Fluoro-6-methylpyridin-2-yl)-5-(N-(−3-hydroxycyclobutylsulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₅S 409.11, m/z found 410.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.17-8.06 (m, 2H),7.93-7.83 (m, 2H), 7.72 (t, J=8.9 Hz, 1H), 7.39 (d, J=9.0 Hz, 1H), 5.02(d, J=5.6 Hz, 1H), 4.02 (s, 3H), 3.71-3.62 (m, 1H), 3.14-3.04 (m, 1H),2.41 (d, J=2.7 Hz, 3H), 2.29-2.19 (m, 2H), 1.64-1.51 (m, 2H).

Compound 142a:N-(3-(difluoromethyl)-4-fluorophenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₅S 444.10, m/z found 445.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.48 (br.s, 1H), 8.07 (d, J=3.6 Hz,1H), 7.95 (d, J=2.4 Hz, 1H), 7.92-7.82 (m, 3H), 7.43-7.10 (m, 3H), 4.96(d, J=4.8 Hz, 1H), 4.15-4.08 (m, 1H), 3.96 (s, 3H), 3.75-3.65 (m, 1H),2.02-1.85 (m, 4H).

Compound 142b:N-(3-(difluoromethyl)-4-fluorophenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₅S 444.10, m/z found 445.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.48 (br.s, 1H), 8.08 (dd, J=2.4Hz, J=6.0 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.92-7.80 (m, 3H), 7.43-7.10(m, 3H), 5.03 (d, J=5.6 Hz, 1H), 3.96 (s, 3H), 3.70-3.60 (m, 1H),3.15-3.05 (m, 1H), 2.30-2.18 (m, 2H), 1.62-1.50 (m, 2H).

Compound 143a:N-(4-chloro-2-fluorophenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.23 (br.s, 1H), 8.21 (d, J=2.8 Hz,1H), 8.11 (t, J=8.8 Hz, 1H), 7.96-7.88 (m, 2H), 7.59 (dd, J=2.4 Hz,J=10.4 Hz, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.36-7.30 (m, 1H), 4.96 (d,J=4.8 Hz, 1H), 4.15-4.09 (m, 1H), 4.05 (s, 3H), 3.76-3.65 (m, 1H),2.00-1.85 (m, 4H).

Compound 143b:N-(4-chloro-2-fluorophenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.24 (br.s, 1H), 8.23 (d, J=2.0 Hz,1H), 8.11 (t, J=8.8 Hz, 1H), 7.96-7.88 (m, 2H), 7.59 (dd, J=2.0 Hz,J=10.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.36-7.30 (m, 1H), 5.03 (d,J=5.2 Hz, 1H), 4.05 (s, 3H), 3.70-3.60 (m, 1H), 3.15-3.05 (m, 1H),2.30-2.18 (m, 2H), 1.62-1.50 (m, 2H).

Compound 144a:N-(2-chloro-4-fluorophenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) 10.38 (br.s, 1H), 8.37 (d, J=2.8 Hz,1H), 8.29 (dd, J=5.6 Hz, J=8.8 Hz, 1H), 8.00-7.90 (m, 2H), 7.62 (dd,J=2.8 Hz, J=8.4 Hz, 1H), 7.48 (d, J=8.8 Hz, 1), 7.31 (td, J=2.8 Hz,J=8.8 Hz, 1H), 4.94 (d, J=4.8 Hz, 1H), 4.13 (s, 3H), 4.16-4.06 (m, 1H),3.76-3.65 (m, 1H), 2.00-1.85 (m, 4H).

Compound 144b:N-(2-chloro-4-fluorophenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.0[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) 10.38 (br.s, 1H), 8.39 (d, J=2.8 Hz,1H), 8.29 (dd, J=2.0 Hz, J=9.2 Hz, 1H), 8.00-7.85 (m, 2H), 7.62 (dd,J=2.8 Hz, J=8.4 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.31 (td, J=2.8 Hz,J=8.8 Hz, 1H), 5.02 (d, J=5.6 Hz, 1H), 4.13 (s, 3H), 3.70-3.60 (m, 1H),3.16-3.06 (m, 1H), 2.30-2.18 (m, 2H), 1.62-1.50 (m, 2H).

Compound 145a:N-(2,4-difluorophenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 413.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.12 (br.s, 1H), 8.19 (d, J=2.4 Hz,1H), 8.04-7.86 (m, 3H), 7.45-7.35 (m, 2H), 7.19-7.10 (m, 1H), 4.95 (d,J=4.8 Hz, 1H), 4.16-4.06 (m, 1H), 4.04 (s, 3H), 3.75-3.65 (m, 1H),2.00-1.82 (m, 4H).

Compound 145b:N-(2,4-difluorophenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈F₂N₂O₅S 412.09, m/z found 413.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.12 (br.s, 1H), 8.22 (d, J=2.8 Hz,1H), 8.04-7.86 (m, 3H), 7.45-7.35 (m, 2H), 7.19-7.10 (m, 1H), 5.03 (d,J=5.6 Hz, 1H), 4.04 (s, 3H), 3.70-3.60 (m, 1H), 3.15-3.05 (m, 1H),2.30-2.18 (m, 2H), 1.62-1.50 (m, 2H).

Compound 146a:N-(2-chloro-5-fluorophenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.62 (br.s, 1H), 8.44 (d, J=2.4 Hz,1H), 8.33 (dd, J=3.2 Hz, J=11.2 Hz, 1H), 8.04-7.94 (m, 2H), 7.68-7.60(m, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.15-7.05 (m, 1H), 4.95 (d, J=5.2 Hz,1H), 4.16 (s, 3H), 4.15-4.05 (m, 1H), 3.78-3.65 (m, 1H), 2.00-1.85 (m,4H).

Compound 146b:N-(2-chloro-5-fluorophenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₈ClFN₂O₅S 428.06, m/z found 429.1[M+H]⁺. 1H NMR (400 MHz, DMSO-d₆) δ 10.63 (br.s, 1H), 8.45 (d, J=2.4 Hz,1H), 8.33 (dd, J=2.8 Hz, J=11.2 Hz, 1H), 8.02-7.92 (m, 2H), 7.70-7.62(m, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.15-7.05 (m, 1H), 5.03 (d, J=5.6 Hz,1H), 4.17 (s, 3H), 3.70-3.60 (m, 1H), 3.15-3.05 (m, 1H), 2.30-2.18 (m,2H), 1.62-1.50 (m, 2H).

Compound 147a:(S)—N-(2,4-Difluorophenyl)-2-methoxy-5-(N-(1-(2-methoxyethoxy)propan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): RT=5.06 min, mass calcd. for C₂₀H₂₄F₂N₂O₆S 458.13, m/zfound 459.1 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.26 (d,J=2.0 Hz, 1H), 8.04-7.94 (m, 2H), 7.72 (s, 1H), 7.47-7.35 (m, 2H), 7.15(t, J=8.3 Hz, 1H), 4.05 (s, 3H), 3.41-3.38 (m, 2H), 3.36-3.31 (m, 2H),3.31-3.23 (m, 2H), 3.20 (s, 3H), 3.18-3.13 (m, 1H), 0.93 (d, J=6.0 Hz,3H).

Compound 147b:(R)—N-(2,4-Difluorophenyl)-2-methoxy-5-(N-(1-(2-methoxyethoxy)propan-2-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₄F₂N₂O₆S 458.13, m/z found 459.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.26 (d, J=2.4 Hz,1H), 8.05-7.93 (m, 2H), 7.71 (d, J=6.8 Hz, 1H), 7.46-7.34 (m, 2H), 7.14(t, J=8.2 Hz, 1H), 4.04 (s, 3H), 3.39-3.36 (m, 2H), 3.36-3.31 (m, 2H),3.31-3.22 (m, 2H), 3.20 (s, 3H), 3.18-3.13 (m, 1H), 0.92 (d, J=6.4 Hz,3H).

Compound 148: N-(2,4-Difluorophenyl)-2-methoxy-5-sulfamoylbenzamide

LC-MS (ESI): R_(T)=4.23 min, mass calcd. for C₁₄H₁₂F₂N₂O₄S 342.05, m/zfound 343.0 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.28 (d,J=2.5 Hz, 1H), 8.03-7.93 (m, 2H), 7.45-7.35 (m, 4H), 7.18-7.10 (m, 1H),4.03 (s, 3H).

Compound 149:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(2-(trifluoromethyl)phenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₅S 444.10, m/z found 445.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (br.s, 1H), 8.40 (d, J=2.0 Hz,1H), 8.11 (d, J=8.0 Hz, 1H), 8.01 (dd, J=8.0 Hz, J=2.0 Hz, 2H), 7.80 (d,J=8.0 Hz, 1H), 7.75 (t, J=8.0 Hz, 1H), 7.53-7.40 (m, 2H), 4.08 (s, 3H),3.75-3.64 (m, 2H), 3.63-2.53 (m, 2H), 3.43-3.35 (m, 1H), 1.94-1.84 (m,1H), 1.65-1.54 (m, 1H).

Compound 150:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(2-(trifluoromethoxy)phenyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₆S 460.09, m/z found 461.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (br.s, 1H), 8.43-8.30 (m, 2H),8.06-7.96 (m, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 7.30(t, J=8.0 Hz, 1H), 4.10 (s, 3H), 3.75-3.64 (m, 2H), 3.63-2.53 (m, 2H),3.43-3.35 (m, 1H), 1.94-1.84 (m, 1H), 1.65-1.54 (m, 1H).

Compound 151:(S)—N-(2-Cyclopropylphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₁H₂₄N₂O₅S 416.14, m/z found 417.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.06(d, J=8.0 Hz, 1H), 8.01-7.95 (m, 2H), 7.47 (d, J=9.0 Hz, 1H), 7.28-7.21(m, 1H), 7.17-7.08 (m, 2H), 4.08 (s, 3H), 3.74-3.55 (m, 4H), 3.40-3.37(m, 1H), 2.05-1.85 (m, 2H), 1.71-1.57 (m, 1H), 1.04-0.96 (m, 2H),0.72-0.62 (m, 2H).

Compound 152:N-(4-Fluorophenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₅S 394.10, m/z found 395.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (br.s, 1H), 7.95 (d, J=2.0 Hz,1H), 7.91-7.82 (m, 2H), 7.78-7.70 (m, 2H), 7.36 (d, J=8.8 Hz, 1H), 7.20(t, J=8.8 Hz, 2H), 4.95 (d, J=5.2 Hz, 1H), 4.17-4.09 (m, 1H), 3.96 (s,3H), 3.74-3.66 (m, 1H), 2.02-1.84 (m, 4H).

Compound 153:N-(4-Fluorophenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉FN₂O₅S 394.10, m/z found 395.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (br.s, 1H), 7.97 (d, J=2.4 Hz,1H), 7.91-7.81 (m, 2H), 7.78-7.71 (m, 2H), 7.36 (d, J=9.2 Hz, 1H), 7.20(t, J=8.8 Hz, 2H), 5.03 (d, J=5.6 Hz, 1H), 3.97 (s, 3H), 3.70-3.61 (m,1H), 3.14-3.04 (m, 1H), 2.28-2.18 (m, 2H), 1.63-1.52 (m, 2H).

Compound 154:N-(2-Chlorophenyl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₅S 410.07, m/z found 411.0[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (br.s, 1H), 8.43 (d, J=2.0 Hz,1H), 8.39 (d, J=8.4 Hz, 1H), 8.00-7.93 (m, 2H), 7.60 (dd, J=8.0 Hz,J=1.6 Hz, 1H), 7.50 (d, J=9.2 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.25-7.19(m, 1H), 4.96 (d, J=5.2 Hz, 1H), 4.16 (s, 3H), 4.14-4.09 (m, 1H),3.78-3.69 (m, 1H), 2.01-1.93 (m, 2H), 1.93-1.85 (m, 2H).

Compound 155:N-(2-Chlorophenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClN₂O₅S 410.07, m/z found 411.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (br.s, 1H), 8.45 (d, J=2.4 Hz,1H), 8.40 (d, J=8.0 Hz, 1H), 8.01-7.90 (m, 2H), 7.60 (dd, J=8.0 Hz,J=1.2 Hz, 1H), 7.49 (d, J=9.2 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.25-7.19(m, 1H), 5.02 (d, J=5.2 Hz, 1H), 4.16 (s, 3H), 3.72-3.61 (m, 1H),3.19-3.03 (m, 1H), 2.29-2.19 (m, 2H), 1.64-1.52 (m, 2H).

Compound 156: N-(5-Fluoropyridin-2-yl)-5-(N-((trans)-3-hydroxycyclobutylsulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₈FN₃O₅S 395.10, m/z found 396.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (br.s, 1H), 8.39 (d, J=2.8 Hz,1H), 8.32-8.24 (m, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.93-7.87 (m, 2H),7.86-7.80 (m, 1H), 7.41 (d, J=8.8 Hz, 1H), 4.95 (d, J=4.8 Hz, 1H),4.16-4.09 (m, 1H), 4.02 (s, 3H), 3.75-3.67 (m, 1H), 2.01-1.93 (m, 2H),1.92-1.85 (m, 2H).

Compound 157:N-(5-Fluoropyridin-2-yl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

LC-MS (ESI): mass calcd. for C₁₇H18FN₃O₅S 395.10, m/z found 396.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (br.s, 1H), 8.39 (d, J=2.8 Hz,1H), 8.32-8.25 (m, 1H), 8.15 (d, J=2.4 Hz, 1H), 7.95-7.79 (m, 3H), 7.40(d, J=8.8 Hz, 1H), 5.02 (d, J=5.6 Hz, 1H), 4.03 (s, 3H), 3.71-3.59 (m,1H), 3.15-3.04 (m, 1H), 2.28-2.18 (m, 2H), 1.63-1.52 (m, 2H).

Compound 158:(S)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H19FN₂O₅S 394.10, m/z found 395.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (br.s, 1H), 8.00 (d, J=2.5 Hz,1H), 7.96-7.84 (m, 2H), 7.80-7.70 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.20(t, J=9.0 Hz, 2H), 3.97 (s, 3H), 3.74-3.65 (m, 2H), 3.64-3.55 (m, 2H),3.39-3.37 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.57 (m, 1H).

Compound 159:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl-N-(m-tolyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂N₂O₅S 390.12, m/z found 391.1 [M+H]⁺,¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (br.s, 1H), 8.00 (d, J=2.3 Hz, 1H),7.95-7.88 (m, 2H), 7.55-7.53 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.23 (t,J=7.8 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H), 3.97 (s, 3H), 3.74-3.66 (m, 2H),3.65-3.56 (m, 2H), 3.40-3.35 (m, 1H), 2.31 (s, 3H), 1.97-1.83 (m, 1H),1.72-1.54 (m, 1H).

Compound 160:(S)—N-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈F₄N₂O₅S 462.09, m/z found 463.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (br.s, 1H), 8.26-8.20 (m, 1H),8.04-7.90 (m, 4H), 7.54 (t, J=9.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 3.97(s, 3H), 3.74-3.66 (m, 2H), 3.65-3.55 (m, 2H), 3.39-3.36 (m, 1H),1.96-1.85 (m, 1H), 1.69-1.57 (m, 1H).

Compound 161(S)—N-(5-Fluoro-4-methylpyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₅S 409.11, m/z found 410.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (br.s, 1H), 8.27 (s, 1H), 8.19(d, J=4.8 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.94(d, J=2.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 3.73-3.64 (m,2H), 3.64-3.55 (m, 2H), 3.39-3.38 (m, 1H), 2.34 (s, 3H), 1.96-1.85 (m,1H), 1.67-1.59 (m, 1H).

Compound 162:(S)—N-(6-Cyclopropyl-5-fluoropyridin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₂₂FN₃O₅S 435.13, m/z found 436.0[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (br.s, 1H), 8.11 (s, 1H),8.02-7.87 (m, 3H), 7.68 (t, J=9.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.00(s, 3H), 3.73-3.64 (m, 2H), 3.64-3.54 (m, 2H), 3.42-3.38 (m, 1H),2.25-2.23 (m, 1H), 1.96-1.83 (m, 1H), 1.67-1.55 (m, 1H), 1.07-0.97 (m,4H).

Compound 163:(S)-2-Methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)-N-(o-tolyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂N₂O₅S 390.12, m/z found 391.1 [M+H]⁺,¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (br.s, 1H), 8.29 (s, 1H), 8.02-7.92 (m,2H), 7.84 (d, J=7.6 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.33-7.21 (m, 2H),7.14 (t, J=7.2 Hz, 1H), 4.09 (s, 3H), 3.75-3.55 (m, 4H), 3.38-3.30 (m,1H), 2.33 (s, 3H), 1.97-1.85 (m, 1H), 1.69-1.59 (m, 1H).

Compound 164:(S)—N-(2-Cyanophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-ylsulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉N₃O₅S 401.10, m/z found 402.1 [M+H]⁺,¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (br.s, 1H), 8.37 (br.s, 1H), 8.21 (d,J=8.4 Hz, 1H), 8.06-7.97 (m, 2H), 7.89 (d, J=7.2 Hz, 1H), 7.77 (t, J=7.6Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 4.12 (s, 3H),3.74-3.56 (m, 4H), 3.39-3.35 (m, 1H), 1.95-1.85 (m, 1H), 1.68-1.58 (m,1H).

Compound 165:(S)-2-Methoxy-N-(pyrimidin-4-yl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₆H₁₈N₄O₅S 378.10, m/z found 379.1 [M+H]⁺,¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (br.s, 1H), 8.94 (br.s, 1H), 8.75 (d,J=5.6 Hz, 1H), 8.21 (d, J=5.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.01-7.91(m, 2H), 7.42 (d, J=8.8 Hz, 1H), 4.01 (s, 3H), 3.74-3.66 (m, 2H),3.65-3.56 (m, 2H), 3.39-3.36 (m, 1H), 1.97-1.85 (m, 1H), 1.69-1.57 (m,1H).

Compound 166:(S)-2-Methoxy-N-(2-methoxyphenyl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂N₂O₆S 406.12, m/z found 407.1 [M+H]⁺,¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (br.s, 1H), 8.52 (d, J=2.4 Hz, 1H),8.44 (d, J=8.0 Hz, 1H), 8.04-7.96 (m, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.12(d, J=3.6 Hz, 2H), 7.03-6.96 (m, 1H), 4.18 (s, 3H), 3.97 (s, 3H),3.73-3.65 (m, 2H), 3.64-3.54 (m, 2H), 3.38-3.35 (m, 1H), 1.94-1.84 (m,1H), 1.66-1.57 (m, 1H).

Compound 167:(S)—N-(3-(Difluoromethyl)-4-fluorophenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₉F₃N₂O₅S 444.10, m/z found 445.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (br.s, 1H), 8.07 (d, J=2.0 Hz,1H), 8.03-7.97 (m, 1H), 7.96-7.88 (m, 2H), 7.86-7.82 (m, 1H), 7.43-7.35(m, 2H), 7.40-7.07 (m, 1H), 3.97 (s, 3H), 3.75-3.65 (m, 2H), 3.65-3.55(m, 2H), 3.40-3.35 (m, 1H), 1.95-1.85 (m, 1H), 1.70-1.55 (m, 1H).

Compound 168:N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(1-(trifluoromethyl)cyclopropyl)sulfamoyl)benzamide

3-((5-fluoro-6-methylpyridin-2-yl)carbamoyl)-4-methoxybenzene-1-sulfonylchloride (200 mg, 0.557 mmol) was added to a solution consisting of1-(trifluoromethyl)cyclopropan-1-amine and pyridine (2 mL) at 0° C. Themixture was stirred overnight at 20° C. The mixture was concentrated todryness to give a residue which was purified by flash columnchromatography over silica gel (eluent: petroleum ether:ethyl acetatefrom 100:0 to 50:50) to give the title compound (100 mg, purity 99.99%,40% yield). LC-MS (ESI): RT=4.89 min, mass calcd. for C₁₈H₁₇F₄N₃O₄S447.09, m/z found 448.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s,1H), 9.14 (br. s., 1H), 8.18-8.03 (m, 2H), 7.90 (dd, J=2.0, 8.5 Hz, 1H),7.72 (t, J=9.0 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 4.02 (s, 3H), 2.41 (d,J=2.0 Hz, 3H), 1.21-1.12 (m, 2H), 1.07-0.96 (m, 2H).

Synthetic Routes for Compound 168-170

Intermediate 169.2: (tert-Butyl3-(3-((5-fluoro-6-methylpyridin-2-yl)carbamoyl)-4-methoxyphenylsulfonamido)azetidine-1-carboxylate

3-((5-Fluoro-6-methylpyridin-2-yl)carbamoyl)-4-methoxybenzene-1-sulfonylchloride (600 mg, 1.34 mmol, purity 80%) was dissolved in dry DCM (5mL). tert-Butyl 3-aminoazetidine-1-carboxylate (461 mg, 2.68 mmol) andTEA (406 mg, 4.01 mmol) were added to the above mixture at 20° C. Themixture was stirred at 20° C. for 1 h. The resultant mixture wasextracted with ethyl acetate (5 mL×3). The combined organic layers wereconcentrated to dryness. The residue was purified by flash columnchromatography over silica gel (eluent: petroleum ether:ethyl acetatefrom 100:0 to 0:100) to afford the title compound (500 mg, 64% yield,purity 85%). LC-MS (ESI): RT=0.78 min, mass calcd. for C₂₂H₂₇FN₄O₆S494.16, m/z found 495.0 [M+H]⁺.

Compound 169:5-(N-(Azetidin-3-yl)sulfamoyl)-N-(5-fluoro-6-methylpyridin-2-yl)-2-Methoxybenzamide

tert-Butyl-3-(3-((5-fluoro-6-methylpyridin-2-yl)carbamoyl)-4-methoxyphenylsulfonamido)azetidine-1-carboxylatewas dissolved in HCl/dioxane (4N, 10 mL). The reaction was stirred at20° C. for 12 h before concentrating it to dryness. The mixture wasadjusted to pH 7˜8 with saturated aq. Na₂CO₃. Water (10 mL) was added.The precipitate was collected, dried and then recrystallized from DMF(20 mL) to afford the title compound (300 mg, 85% yield).

LC-MS (ESI): RT=4.05 min, mass calcd. for C₁₇H₁₉FN₄O₄S 394.11, m/z found395.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (s, 1H), 9.38 (br. s.,1H), 8.87 (br. s., 1H), 8.12-8.05 (m, 2H), 7.94 (dd, J=2.5, 8.8 Hz, 1H),7.71 (t, J=9.0 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 4.13 (d, J=7.0 Hz, 1H),4.00 (s, 3H), 3.88-3.81 (m, 2H), 3.79-3.71 (m, 2H), 2.40 (d, J=2.8 Hz,3H).

Compound 170:N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(1-methylazetidin-3-yl)sulfamoyl)benzamide

5-(N-(Azetidin-3-yl)sulfamoyl)-N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxybenzamide(120 mg, 0.304 mmol) was dissolved in methanol (2 mL) in a 50 mLround-bottomed flask and then treated with formaldehyde (49.3 mg, 0.608mmol, w/w 37%). The mixture was stirred at 20° C. for 30 minutes beforeNaBH₃CN (57.3 mg, 0.912 mmol) was added. The reaction mixture wasstirred at room temperature for 1 h and then concentrated to drynessunder reduced pressure. Ethyl acetate (20 mL) was added. The resultantmixture was washed with water (20 mL), brine (20 mL), dried over Na₂SO₄and filtered. The filtrate was concentrated to dryness to give a residuewhich was further purified by prep.HPLC (Waters Xbridge Prep OBD C18 150mm*30 mm, 5 um (eluent: CH₃CN/H₂O (10 mM NH₄HCO₃-ACN) from 25% to 55%,flow rate: 30 ml/min) to afford the title compound (14.2 mg, 11% yield).

LC-MS (ESI): RT=3.89 min, mass calcd. for C₁₈H₂₁FN₄O₄S 408.13, m/z found409.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d) δ 10.61 (s, 1H), 8.18 (br. s.,1H), 8.09 (d, J=2.3 Hz, 2H), 7.90 (dd, J=2.5, 8.8 Hz, 1H), 7.72 (t,J=9.0 Hz, 1H), 7.38 (d, J=9.0 Hz, 1H), 4.01 (s, 3H), 3.69 (br. s., 1H),3.33-3.30 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 2.41 (d, J=2.8 Hz, 3H), 2.13(s, 3H).

Compound 171:(S)—N-(4-chloro-5-fluoro-6-methylpyrimidin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

(5)-Methyl 2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate (300mg, 0.95 mmol) and 4-chloro-5-fluoro-6-methylpyrimidin-2-amine (207 mg,1.05 mmol) were dissolved in dry THF (5 mL) followed by the addition oftrimethylaluminum (1.90 mL) drop-wise at 0° C. The reaction mixture wasstirred at room temperature for 30 min and then quenched with saturatedNH₄Cl (5 mL). The organic phase was separated, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to give aresidue which was purified by prep.TLC to give the title compound (39.10mg, yield: 9.25%) as a pale-yellow solid.

LC-MS (ESI): R_(T)=4.18 min, mass calcd. for C₁₇H₁₈ClFN₄O₅S 444.07, m/zfound 445.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d) δ 11.15 (br.s, 1H),8.07-7.73 (m, 3H), 7.32 (d, J=7.2 Hz, 1H), 3.88 (s, 3H), 3.75-3.64 (m,2H), 3.63-2.53 (m, 2H), 3.40-3.35 (m, 1H), 2.46-2.36 (m, 3H), 1.94-1.84(m, 1H), 1.65-1.54 (m, 1H).

Compound 172:(S)—N-(5-fluoro-4-methylpyrimidin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

(S)—N-(4-chloro-5-fluoro-6-methylpyrimidin-2-yl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide(300 mg, 0.67 mmol) and TEA (1 mL) were dissolved in MeOH (5 mL)followed by the addition of Pd/C (50 mg, 10% w/w). The reaction mixturewas stirred at room temperature for 16 hours under H₂ (30 psi) and thenfiltered. The filtrate was concentrated under reduced pressure to give aresidue which was triturated with DCM (2-3 mL). The solid was filteredand then dried in vacuum to give the title compound (47.50 mg, yield:17.06%) as a brown solid.

LC-MS (ESI): R_(T)=3.67 min, mass calcd. for C₁₇H₁₉FN₄O₅S 410.11, m/zfound 411.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (br.s, 1H), 8.59(br.s, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.91 (dd, J=8.8 Hz, J=2.4 Hz, 2H),7.32 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.75-3.64 (m, 2H), 3.63-2.53 (m,2H), 3.40-3.35 (m, 1H), 2.46-2.36 (m, 3H), 1.94-1.84 (m, 1H), 1.65-1.54(m, 1H).

Compound 173:N-(2,4-Difluoro-3-methylphenyl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

To a solution consisting of 2,4-difluoro-3-methylaniline (95 mg, 0.664mmol), triethylamine (0.14 mL, 1.00 mmol), HATU (252 mg, 0.664 mmol) andDCM (2 mL) was added5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzoic acid (106mg, 0.332 mmol) under 0° C. The reaction mixture was stirred at 25° C.for 3 h. The resulting mixture was concentrated. The residue waspurified by prep.HPLC (eluent: CH₃CN/H₂O (0.05% HCl) from 37% to 77%,v/v). The pure fractions were collected and the solvent was evaporatedunder vacuum. The aqueous layer was lyophilized to dryness to give titlecompound as a white powder (15.60 mg, 97.62% purity, 10.84% yield).

LC-MS (ESI): R_(T)=4.84 min, mass calcd. for C₁₉H₂₀F₂N₂O₅S 426.1, m/zfound 427.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H), 8.23 (d,J=2.0 Hz, 1H), 7.98-7.79 (m, 3H), 7.42 (d, J=9.0 Hz, 1H), 7.10 (t, J=9.3Hz, 1H), 5.03 (d, J=5.5 Hz, 1H), 4.05 (s, 3H), 3.72-3.59 (m, 1H),3.16-3.03 (m, 1H), 2.28-2.16 (m, 5H), 1.65-1.49 (m, 2H).

Compound 174a-174b

Intermediate 174.2: 6-Chloro-2-(difluoromethyl)-3-fluoropyridine

To a solution consisting of 6-chloro-3-fluoropicolinaldehyde (1.0 g,6.27 mmol) and DCM (20 mL) was added DAST (1.5 g, 9.32 mmol) at 0° C.The reaction was stirred at room temperature overnight. The reactionmixture was diluted with DCM (20 mL) and then quenched with sat. NaHCO₃(20 mL). The organic layer was separated, washed with brine (20 mL),dried over Na₂SO₄ and filtered. The filtrate was concentrated to drynessto give compound the title compound (1 g, 88% yield). ¹H NMR (400 MHz,CDCl₃) δ 7.56-7.46 (m, 2H), 6.71 (t, J=53.2 Hz, 1H).

Intermediate 174.3:6-(Difluoromethyl)-N-(diphenylmethylene)-5-fluoropyridin-2-amine

6-Chloro-2-(difluoromethyl)-3-fluoropyridine (700 mg, 3.86 mmol),diphenylmethanimine (1.40 g, 7.73 mmol), Cs₂CO₃ (2.51 g, 7.70 mmol),Pd(OAc)₂ (86 mg, 0.38 mmol) and BINAP (240 mg, 0.38 mmol) was suspendedin dry dioxane (15 mL). The resultant reaction mixture was stirred at100° C. overnight under N₂. The mixture was then concentrated in vacuum.The residue was diluted with DCM (40 mL) and then filtered. The filtratewas concentrated to give the title compound (2.5 g, crude) as brown oil,which was used directly for next step.

Preparation of Compound 174.4:6-(Difluoromethyl)-5-fluoropyridin-2-amine

HCl (1 M, 20 mL, 20 mmol) was added to a solution consisting of6-(difluoromethyl)-N-(diphenylmethylene)-5-fluoropyridin-2-amine (2.5 g,crude) and THF (20 mL). The mixture was stirred at 25° C. for 1 h beforeconcentrating it to dryness. The residue was purified by prep-HPLC togive the title compound (600 mg) as a light yellow solid.

Compound 174a:N-(6-(Difluoromethyl)-5-fluoropyridin-2-yl)-5-(N-((trans)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamideCompound 174b:N-(6-(Difluoromethyl)-5-fluoropyridin-2-yl)-5-(N-((cis)-3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzamide

To a solution consisting of methyl5-(N-(3-hydroxycyclobutyl)sulfamoyl)-2-methoxybenzoate (200 mg, 0.634mmol), 6-(difluoromethyl)-5-fluoropyridin-2-amine (525 mg, 1.901 mmol)and dry dioxane (6 mL) was added Me₃Al (2 M solution, 1.9 mL, 3.8 mmol)drop-wise at 25° C. The mixture was stirred at 50° C. for 2 hrs. Aftercooling to room temperature, the mixture was quenched with water (0.5mL), then diluted with MeOH (20 mL) and filtered. The filtrate wasconcentrated to dryness. The residue was purified by prep-HPLC (NH₃.H₂Oas additive) to give the racemic mixture as a white solid. The racemicmixture was separated by SFC (separation condition: Column: ChiralPakAD, Daicel Chemical Industries, Ltd, 250×30 mm I.D., 10 μm; Mobilephase: A: Supercritical CO₂, B: ethanol (0.1% NH₃.H₂O), A:B=75:25 at 80mL/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60°C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.; Wavelength: 220 nm)to give 174a (16.20 mg purity 96.8%, yield: 5.52%) and 174b (77.10 mgpurity 99.9%, yield: 27.29%).

Analytic data of 174a: LC-MS (ESI): R₁=4.33 min, mass calcd. forC₁₈H₁₈F₃N₃O₅S 445.09, m/z found 446.1 [M+H]⁺. 1H NMR (400 MHz, DMSO-d₆)δ 10.95 (br.s, 1H), 8.47-8.40 (m, 1H), 8.08-8.00 (m, 2H), 7.90-7.85 (m,2H), 7.38 (d, J=8.8 Hz, 1H), 7.11 (t, J=52.8 Hz, 1H), 4.95 (d, J=5.2 Hz,1H), 4.16-4.08 (m, 1H), 3.99 (s, 3H), 3.75-3.65 (m, 1H), 2.02-1.85 (m,4H);

Analytic data of 174b: LC-MS (ESI): R_(T)=4.54 min, mass calcd. forC₁₈H₁₈F₃N₃O₅S 445.09, m/z found 446.1 [M+H]⁺. 1H NMR (400 MHz, DMSO-d₆)δ 10.95 (br.s, 1H), 8.47-8.40 (m, 1H), 8.08-8.00 (m, 2H), 7.93-7.82 (m,2H), 7.38 (d, J=8.8 Hz, 1H), 7.11 (t, J=53.2 Hz, 1H), 5.02 (d, J=5.6 Hz,1H), 3.99 (s, 3H), 3.70-3.60 (m, 1H), 3.16-3.04 (m, 1H), 2.30-2.20 (m,2H), 1.64-1.52 (m, 2H).

Compound 175

Intermediate 175.2: (S)-tert-Butyl3-(3-((5-fluoro-6-methylpyridin-2-yl)carbamoyl)-4-methoxyphenylsulfonamido)pyrrolidine-1-carboxylate

3-((5-Fluoro-6-methylpyridin-2-yl)carbamoyl)-4-methoxybenzene-1-sulfonylchloride (1.0 g, 2.23 mmol) was dissolved in dry DCM (10 mL).(S)-tert-Butyl 3-aminopyrrolidine-1-carboxylate (498 mg, 2.68 mmol) andTEA (677 mg, 6.69 mmol) were added to the above mixture at 0° C. Themixture was stirred at 20° C. for 4 h. The mixture was washed with H₂O(20 mL), dried over sodium sulfate, filtered and concentrated. Theresidue was purified by flash column over silica gel (gradient eluent:petroleum ether:ethyl acetate from 100:0 to 0:100). The residue wascrystallized from ethyl acetate to afford the title compound (600 mg,50% yield).

LC-MS (ESI): RT=0.76 min, mass calcd. for C₂₃H₂₉FN₄O₆S 508.2, m/z found509.2 [M+H]⁺.

Compound 175:(S)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

(S)-tert-Butyl-3-(3-((5-fluoro-6-methylpyridin-2-yl)carbamoyl)-4-methoxyphenylsulfonamido)pyrrolidine-1-carboxylate was dissolved in HCl/dioxane (10 mL). Thereaction was stirred at 20° C. for 4 h, the solvent was concentrated invacuum. The residue was dissolved in DMSO (10 mL). Aqueous Na₂CO₃ (1N)was added drop-wise with stirring till PH=7 at 20° C. Then a whiteprecipitate formed. The precipitate was filtered off and dried to affordthe title compound (400 mg, 85% yield).

LC-MS (ESI): RT=3.60 min, mass calcd. for C₁₈H₂₁FN₄O₄S 408.1, m/z found409.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s, 1H), 8.16-8.07 (m,2H), 7.93 (dd, J=2.5, 8.8 Hz, 1H), 7.72 (t, J=9.0 Hz, 1H), 7.40 (d,J=9.0 Hz, 1H), 4.02 (s, 3H), 3.50-3.42 (m, 1H), 2.76-2.66 (m, 2H),2.64-2.55 (m, 2H), 2.41 (d, J=2.8 Hz, 3H), 2.39-2.31 (m, 2H), 1.74-1.64(m, 1H), 1.42-1.34 (m, 1H).

Compound 176:(S)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)benzamide

(S)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide(150 mg, 0.367 mmol) was dissolved in methanol (5 mL) in a 50 mLround-bottomed flask and then treated with formaldehyde (59.6 mg, 0.74mmol, purity 37%). The mixture was stirred at 20° C. for 30 minutes.Sodium cyanotrihydroborate (34.6 mg, 0.55 mmol) was added to themixture. The reaction mixture was stirred at room temperature for 1 hand concentrated to dryness under reduced pressure. The crude wascrystallized from a mixture of DMSO:water=1:2. The residue was purifiedby prep.HPLC (column: Synergi Max-RP 200 mm*25 mm, 4 μm; mobile phase:CH₃CN in water (0.075% TFA water) from 18% to 48%, flow rate: 30ml/min). The pure fractions were collected and the volatiles wereremoved under vacuum. The aqueous phase was basified with IM aqueousNa₂CO₃ till pH=7. Ethyl acetate (50 mL) was added. The organic layer wasseparate and filtered. The filtrate was evaporated to dryness undervacuum to afford the title compound (79.8 mg, 52% yield).

LC-MS (ESI): RT=3.65 min, mass calcd. for C₁₉H₂₃FN₄O₄S 422.1, m/z found423.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.14-8.02 (m,2H), 7.94-7.82 (m, 2H), 7.68 (t, J=8.9 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H),3.98 (s, 3H), 3.65-3.56 (m, 1H), 2.68-2.59 (m, 1H), 2.54-2.49 (m, 1H),2.45-2.40 (m, 1H), 2.37 (d, J=2.4 Hz, 3H), 2.33-2.26 (m, 1H), 2.22 (s,3H), 1.94-1.83 (m, 1H), 1.53-1.42 (m, 1H).

Compound 177 to 181 were Synthesized as Similar Procedure to Compound175

Compound 177:(R)—N-(5-Fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₁FN₄O₄S 408.13, m/z found 409.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (s, 1H), 8.14 (d, J=2.5 Hz,1H), 8.09 (d, J=8.3 Hz, 1H), 7.96 (dd, J=2.5, 8.8 Hz, 1H), 7.72 (t,J=9.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 4.02 (s, 3H), 3.73-3.65 (m, 2H),3.13-3.02 (m, 4H), 2.91-2.84 (m, 1H), 2.41 (d, J=2.8 Hz, 3H), 1.95-1.84(m, 1H), 1.74-1.64 (m, 1H).

Compound 178:(S)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₄S 393.12, m/z found 394.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 7.99 (s, 1H), 7.91(d, J=8.8 Hz, 1H), 7.74 (dd, J=5.3, 8.5 Hz, 2H), 7.37 (d, J=8.8 Hz, 1H),7.20 (t, J=8.8 Hz, 2H), 3.96 (s, 3H), 2.79-2.70 (m, 2H), 2.69-2.59 (m,1H), 2.47-2.37 (m, 2H), 1.76-1.65 (m, 1H), 1.48-1.35 (m, 1H).

Compound 179:(S)—N-(2-Chlorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀ClN₃O₄S 409.09, m/z found 410.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.45 (br. s., 1H),8.38 (d, J=7.8 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H),7.50 (d, J=8.5 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.21 (t, J=7.7 Hz, 1H),4.15 (s, 3H), 3.55-3.47 (m, 2H), 2.82-2.72 (m, 2H), 2.70-2.65 (m, 1H),1.78-1.64 (m, 1H), 1.47-1.37 (m, 1H).

Compound 180:(R)—N-(4-Fluorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₂₀FN₃O₄S 393.12, m/z found 394.1[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s, 1H), 8.06 (d, J=1.8 Hz,1H), 7.99 (d, J=8.8 Hz, 1H), 7.81 (dd, J=5.0, 8.8 Hz, 2H), 7.44 (d,J=8.8 Hz, 1H), 7.26 (t, J=8.8 Hz, 2H), 4.03 (s, 3H), 3.66-3.58 (m, 1H),2.97-2.86 (m, 2H), 2.86-2.77 (m, 1H), 2.66-2.57 (m, 1H), 1.89-1.78 (m,1H), 1.61-1.51 (m, 1H).

Compound 181:(R)—N-(3-(Difluoromethyl-4-fluorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀F₃N₃O₄S 443.11, m/z found 444.11[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 8.11-8.05 (m, 1H),8.03-7.98 (m, 1H), 7.97-7.82 (m, 2H), 7.43-7.33 (m, 1), 7.10 (s, 1H),3.97 (s, 3H), 3.56-3.49 (m, 3H), 2.84-2.75 (m, 2H), 2.73-2.65 (m, 1H),1.80-1.65 (m, 1H), 1.51-1.39 (m, 1H).

Compound 182-188

Intermediate 182.2: (S)-tert-butyl 3-(4-methoxy-3-(methoxycarbonyl)phenylsulfonamido) pyrrolidine-1-carboxylate

To a solution consisting of(S)-tert-butyl3-aminopyrrolidine-1-carboxylate (10.0 g, 53.7 mmol), TEA (22.5 mL, 161mmol) and DCM (100 mL) was added methyl5-(chlorosulfonyl)-2-methoxybenzoate (14.2 g, 53.7 mmol) at 0° C. Themixture was stirred at room temperature for 12 hours. Water (60 mL) wasadded. The aqueous layer was extracted with dichloromethane (80 mL*2).The combined organic layers were washed with brine, dried over Na₂SO₄and filtered. The filtrate was concentrated under reduced pressure togive a residue which was purified by silica gel chromatography (elute:petroleum ether:ethyl acetate=3:1) to give title compound (14.5 g, 58.6%yield).

Intermediate 182.3: (S)-tert-butyl3-(3-((2,4-difluorophenyl)carbamoyl)-4-methoxyphenylsulfonamido)pyrrolidine-1-carboxylate

To a solution consisting of (S)-tert-butyl3-(4-methoxy-3-(methoxycarbonyl)phenylsulfonamido)pyrrolidine-1-carboxylate (200 mg, 0.483 mmol)),2,4-difluoroaniline (74.9 mg, 0.580 mmol) and THF (3 mL) was addedLiHMDS (2.42 mL, 2.42 mmol). The mixture was stirred at room temperaturefor 12 hours and then quenched with saturated ammonium chloride. Theorganic layer was separated and dried over Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure to give the titlecompound (250 mg, 78.1% yield).

Compound 182:(S)—N-(2,4-difluorophenyl-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

To a solution consisting of (S)-tert-butyl3-(3-((2,4-difluorophenyl)carbamoyl)-4-methoxyphenylsulfonamido)pyrrolidine-1-carboxylate(250 mg, 0.489 mmol) and ethyl acetate (3 mL) was added HCl/ethylacetate (3 mL, 4N). The mixture was stirred at room temperature for 12hours and then adjusted to pH 7 with saturated sodium bicarbonate. Theaqueous layer was extracted with ethyl acetate (30 mL*2). The combinedorganic layers were washed with brine, dried over Na₂SO₄ and filtered.The filtrate was concentrated under reduced pressure to give a residuewhich was purified by prep.HPLC (Column: Phenomenex Gemini C18 200*25mm*10 um, Flow rate: 25 ml/min, Mobile Phase A: Base water (containing0.05% NH₃.H₂O), Mobile Phase B: Acetonitrile.). The desired fraction wascollected and the volatile was removed under reduced pressure. The waterphase was lyophilized to give the title compound (26.10 mg, 12.3%yield).

LC-MS (ESI): R_(T)=4.74 min, mass calcd. for C₁₈H₁₉F₂N₃O₄S 411.42, m/zfound 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (br.s, 1H), 8.23(d, J=2.0 Hz, 1H), 7.94-8.02 (m, 2H), 7.37-7.45 (m, 2H), 7.14 (t, J=8.0Hz, 1H), 4.04 (s, 3H), 2.61-2.77 (m, 4H), 2.38-2.43 (m, 1H), 1.65-1.74(m, 1H), 1.35-1.43 (m, 1H).

Compound 183-188 were Synthesized as Similar Procedure to Compound 182

Compound 183:(S)—N-(3-(difluoromethyl)-4-fluorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₀F₃N₃O₄S 443.44, m/z found 444.0[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (br.s, 2H), 8.06-8.10 (m, 1H),8.00 (d, J=2.0 Hz, 1H), 7.94 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.84-7.90 (m,1H), 7.36-7.42 (m, 2H), 7.24-7.21 (m, 1H), 3.97 (s, 3H), 2.74-2.94 (m,4H), 2.57-2.63 (m, 1H), 1.74-1.83 (m, 1H), 1.48-1.56 (m, 1H).

Compound 184:(S)-2-methoxy-N-(2-methoxyphenyl)-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₃N₃O₅S 405.47, m/z found 406.2 [M+H]⁺,¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (br.s, 2H), 8.52 (s, 1H), 8.43 (d,J=8.0 Hz, 1H), 7.95-8.02 (m, 1H), 7.50 (d, J=8.8 Hz, 1K), 7.13 (d, J=3.6Hz, 2H), 6.96-7.03 (m, 1H), 4.17 (s, 3H), 3.97 (s, 3H), 2.57-2.80 (m,4H), 2.38-2.44 (m, 1H), 1.65-1.76 (m, 1H), 1.34-1.44 (m, 1H).

Compound 185:(S)—N-(4-chloro-2-fluorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClFN₃O₄S 427.88, m/z found 428.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (br.s, 2H), 8.24 (s, 1H), 8.11(t, J=8.4 Hz, 1H), 7.94-7.99 (m, 1H), 7.57 (d, J=10.4 Hz, 1H), 7.44 (d,J=8.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 4.05 (s, 3H), 2.58-2.78 (m, 4H),2.38-2.42 (m, 1H), 1.64-1.73 (m, 1H), 1.32-1.43 (m, 1H).

Compound 186:(S)—N-(2-chloro-5-fluorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉ClFN₃O₄S 427.88, m/z found 428.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.63 (br.s, 2H), 8.47 (s, 1H), 8.32(d, J=10.4 Hz, 1H), 8.02 (d, J=10.8 Hz, 1H), 7.61-7.67 (m, 1H), 7.51 (d,J=8.8 Hz, 1H), 7.13 (t, J=6.4 Hz, 1H), 4.16 (s, 3H), 2.60-2.89 (m, 4H),1.65-1.85 (m, 2H).

Compound 187:(S)—N-(4-fluoro-3-methylphenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₂₂FN₃O₄S 407.46, m/z found 408.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (br.s, 1H), 7.97-8.02 (m, 1H),7.87-7.95 (m, 1H), 7.61-7.65 (m, 1H), 7.52-7.58 (m, 1H), 7.34-7.41 (m,1H), 7.13 (t, J=9.2 Hz, 1H), 3.97 (s, 3H), 2.58-2.80 (m, 4H), 2.39-2.45(m, 1H), 2.24 (s, 3H), 1.66-1.75 (m, 1H), 1.36-1.45 (m, 1H).

Compound 188:(R)—N-(2,4-difluorophenyl)-2-methoxy-5-(N-(pyrrolidin-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₉F₂N₃O₄S 411.11, m/z found 412.1[M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (br. s., 1H), 8.24 (d, J=2.0Hz, 1H), 8.05-7.90 (m, 2H), 7.49-7.30 (m, 2H), 7.14 (t, J=7.8 Hz, 1H),4.04 (s, 3H), 2.82-2.71 (m, 2H), 2.70-2.61 (m, 2H), 2.44 (m, 1H),1.78-1.65 (m, 1H), 1.41 (m, J=5.8, 13.2 Hz, 1H).

Compound 189

Intermediate 189.2: (S)-Methyl2-methoxy-5-(N-methyl-N-(tetrahydrofuran-3-yl) sulfamoyl) benzoate

(S)-Methyl 2-methoxy-5-(N-(tetrahydrofuran-3-yl) sulfamoyl) benzoate(1.00 g, 3.17 mmol) and potassium carbonate (893 mg, 6.46 mmol) weredissolved in DMF (5 mL) at 0° C. Then iodomethane (539 mg, 3.80 mmol)was added into the mixture and the mixture was stirred at roomtemperature for 2 hours. The mixture was poured into ice water andprecipitation formed. The precipitation was collected. The crude product(1.00 g crude) was used directly for next step without furtherpurification.

Intermediate 189.3: (3S)-2-Methoxy-5-(N-methyl-N-(tetrahydrofuran-3-yl)sulfamoyl) benzoic acid

To a solution consisting of (S)-methyl2-methoxy-5-(N-methyl-N-(tetrahydrofuran-3-yl) sulfamoyl) benzoate (1.00g, 3.04 mmol) in THF (4 mL) and H₂O (1 mL) was added lithium hydroxidehydrate (151 mg, 3.60 mmol). The mixture was stirred at room temperaturefor 2 hours and the resultant solution was concentrated under reducedpressure. The residue was adjusted to pH=5˜6 (1 N HCl) and precipitationformed. The precipitation was collected. The crude product (800 mgcrude) was used directly for next step without further purification.

Intermediate 189.4: (S)-2-Methoxy-5-(N-methyl-N-(tetrahydrofuran-3-yl)sulfamoyl) benzoyl chloride

To a solution of (S)-2-methoxy-5-(N-methyl-N-(tetrahydrofuran-3-yl)sulfamoyl)benzoic acid (300 mg, 0.95 mmol) in DCM (3 mL) was addedoxalyl dichloride (150 mg, 1.18 mmol). The mixture was stirred at roomtemperature for 2 hours and the resultant solution was concentratedunder reduced pressure. The crude product (310 mg crude) was useddirectly for next step without further purification.

Compound 189:(S)—N-(5-fluoro-6-methylpyridin-2-yl)-2-methoxy-5-(N-methyl-N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

(S)-2-Methoxy-5-(N-methyl-N-(tetrahydrofuran-3-yl)sulfamoyl)benzoylchloride (310 mg, 0.93 mmol) was added into a solution consisting of5-fluoro-6-methylpyridin-2-amine (117 mg, 0.93 mmol), triethylamine (202mg, 2.00 mmol) and DCM (3 mL). The reaction was stirred at 25° C. for 2hours. The mixture was concentrated under reduced pressure. The residuewas purified by prep. TLC to give the title compound as a pale-yellowsolid (154.80 mg, 37.4% yield, purity: 95.0%).

LC-MS (ESI): R_(T)=4.71 min, mass calcd. for C₁₉H₂₂FN₃O₅S 423.5, m/zfound 424.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (br.s, 1H), 8.06(d, J=6.4 Hz, 1H), 7.97 (s, 1H), 7.90 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.69(t, J=8.8 Hz, 1H), 7.36 (d, J=4.8 Hz, 1H), 4.59-4.49 (m, 2H), 3.98 (s,3H), 3.81-3.69 (m, 2H), 3.55-3.45 (m, 1H), 2.62 (s, 3H), 2.42-2.32 (m,3H), 1.94-1.84 (m, 1H), 1.56-1.45 (m, 1H).

Compound 190-196

Intermediate 190.2: 4-(Methoxy-d3)-3-(methoxycarbonyl)benzenesulfonicacid

Chlorosulfonic acid (20 mL) was added to methyl 2-(methoxy-d3) benzoate(3.00 g, 17.7 mmol) drop-wise at room temperature. The mixture wasstirred at that temperature for 2 hours and then concentrated underreduced pressure to give the crude product (2.20 g). The residue wasused for next step without further purification.

Intermediate 190.3: Methyl 5-(chlorosulfonyl)-2-(methoxy-d3)benzoate

Sulfurous dichloride (10 mL) was added to4-(methoxy-d3)-3-(methoxycarbonyl) benzenesulfonic acid (2.20 g, 8.83mmol) drop-wise at room temperature. The mixture was stirred at thattemperature for 2 hours and then concentrated under reduced pressure togive the crude product (2.00 g). The residue was used for next stepwithout further purification.

Intermediate 190.4: (S)-Methyl2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate

To a solution consisting of (S)-3-aminotetrahydrofuran hydrochloride(1.01 g, 8.17 mmol, Shanghai Nuohey Chemical Technology CO., LTD.), TEA(2.23 g, 22.04 mmol) and DCM (20 mL) was added methyl5-(chlorosulfonyl)-2-(methoxy-d3) benzoate (2.00 g, 7.47 mmol). Themixture was stirred at room temperature for 2 hours and the resultantsolution was concentrated under reduced pressure. Water and ethylacetate were added. The organic layer was separated and the water phasewas extracted twice with ethyl acetate. The combined organic layers werewashed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to give the title compound (2.00 g,84.09% yield).

Intermediate 190.5:(S)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoic acid

Lithium hydroxide (158 mg, 3.77 mmol) was added into a solutionconsisting of (S)-methyl 2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl) benzoate (2.00 g, 6.28 mmol), THF (4 mL) and H₂O (1 mL). Thereaction mixture was stirred at room temperature for 2 hours beforeconcentrating it under reduced pressure to remove volatiles. Theresultant aqueous phase was adjusted to pH=5-6 with aq. HCl solution andthe precipitation was collected and dried to give the product (1.40 g,73.22% yield).

Intermediate 190.6:(S)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoyl chloride

Oxalyl dichloride (876 mg, 6.90 mmol) was added into a solutionconsisting of (S)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl) sulfamoyl)benzoic acid (1.40 g, 4.60 mmol) and DCM (20 mL). The reaction wasstirred at room temperature for 2 hours. The resultant mixture wasconcentrated under reduced pressure to give the title compound (1.50 gcrude), which was used for the next step directly.

Compound 190:(S)—N-(4-fluorophenyl)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

(S)-2-(Methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoylchloride(200 mg, 0.62 mmol) was dissolved in dry DCM (2 mL) and the resultantsolution was added drop-wise to a well stirred solution consisting of4-fluoroaniline (76.0 mg, 0.68 mmol), TEA (182 mg, 1.80 mmol) and DCM (3mL) at room temperature. The reaction mixture was stirred at roomtemperature for 2 hours and then diluted with DCM (5 mL). Water (5 mL)was added. The organic phase was separated, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to give aresidue which was purified by prep-TLC.

LC-MS (ESI): R_(T)=4.21 min, mass calcd. for C₁₈H₁₆D₃FN₂O₅S 397.44, m/zfound 398.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (br.s, 1H), 8.00(d, J=4.0 Hz, 1H), 7.98-7.86 (m, 2H), 7.81-7.68 (m, 2H), 7.38 (d, J=8.8Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 3.74-3.54 (m, 4H), 3.30-3.20 (m, 1H),1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 191-196 were Synthesized as Similar Procedure to Compound 190

Compound 191:(S)—N-(4-fluoro-3-methylphenyl)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₈D₃FN₂O₅S 411.46, m/z found 412.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (br.s, 1H), 8.00 (d, J=4.0 Hz,1H), 7.98-7.86 (m, 2H), 7.68-7.51 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.13(t, J=8.8 Hz, 1H), 3.74-3.54 (m, 4H), 3.30-3.20 (m, 1H), 2.24 (s, 3H),1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 192:(S)—N-(3-(Difluoromethyl)-4-fluorophenyl)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₉H₁₆D₃F₃N₂S 447.44, m/z found 448.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (br.s, 1H), 8.15-7.77 (m, 5H),7.47-7.32 (m, 2H), 7.25 (t, J=56.0 Hz, 1H), 3.74-3.54 (m, 4H), 3.30-3.20(m, 1H), 1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 193:(S)—N-(5-fluoropyridin-2-yl)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₅D₃FN₃O₅S 398.42, m/z found 399.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (br.s, 1H), 8.44-8.10 (m, 3H),8.03-7.76 (m, 3H), 7.42 (d, J=8.8 Hz, 1H), 3.74-3.54 (m, 4H), 3.30-3.20(m, 1H), 1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 194:(S)—N-(5-fluoro-6-methylpyridin-2-yl)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₈H₁₇D₃FN₃O₅S 412.45, m/z found 413.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.61 (br.s, 1H), 8.14 (d, J=4.0 Hz,1H), 8.10 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8 Hz, J=4.0 Hz, 2H), 7.72 (t,J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 3.74-3.54 (m, 4H), 3.30-3.20 (m,1H), 2.47-2.24 (m, 3H), 1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 195:(S)—N-(6-cyclopropyl-5-fluoropyridin-2-yl)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₂₀H₁₉D₃FN₃O₅S 438.49, m/z found 439.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (br.s, 1H), 8.10 (s, 1H), 7.93(d, J=8.8 Hz, 2H), 7.66 (t, J=9.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H),3.74-3.54 (m, 4H), 3.30-3.20 (m, 1H), 2.32-2.18 (m, 1H), 1.96-1.85 (m,1H), 1.68-1.58 (m, 1H), 1.17-0.76 (m, 4H).

Compound 196:(S)—N-(3,5-difluoropyridin-2-yl)-2-(methoxy-d3)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

LC-MS (ESI): mass calcd. for C₁₇H₁₄D₃F₂N₃O₅S 416.41, m/z found 417.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (br.s, 1H), 8.40 (s, 1H),8.16-8.04 (m, 2H), 8.02-7.92 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 3.75-3.53(m, 4H), 3.40-3.35 (m, 1H), 1.96-1.85 (m, 1H), 1.68-1.58 (m, 1H).

Compound 197

Intermediate 197.2: Methyl 2-isopropoxybenzoate

To a solution consisting of methyl 2-hydroxybenzoate (2.00 g, 13.1mmol), K₂CO₃ (5.45 g, 39.4 mmol) and DMF (20 mL) was added 2-iodopropane(4.47 g, 26.3 mmol). The mixture was stirred at room temperature for 12hours. Water (20 mL) was added into the mixture. The aqueous layer wasextracted with ethyl acetate (40 mL×2). The combined organic layers werewashed with brine (20 mL×2) and dried over Na₂SO₄. The organic layer wasfiltered and concentrated under reduced pressure to give the titlecompound. (2.00 g, 78.3% yield).

Intermediate 197.3: Methyl 5-(chlorosulfonyl)-2-hydroxybenzoate

To a solution consisting of methyl 2-isopropoxybenzoate (1.00 g, 5.15mmol) and sulfurous dichloride (8 mL) was added sulfurochloridic acid(0.847 mL, 12.9 mmol) at 0° C. The mixture was stirred at roomtemperature for 12 hours. The reaction mixture was poured into icewater. The title compound was precipitated and filtered. (1.00 g, 77.5%yield) ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J=2.4 Hz, 1H), 7.70 (dd,J=2.4, 8.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.89 (s, 3H).

Intermediate 197.4; (S)-Methyl2-hydroxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate

To a solution consisting of (S)-3-aminotetrahydrofuran hydrochloride(172 mg, 1.40 mmol, Shanghai Nuohey Chemical Technology CO., LTD.), TEA(0.584 mL, 4.19 mmol) and DCM (5 mL) was added methyl5-(chlorosulfonyl)-2-hydroxybenzoate (350 mg, 1.40 mmol). The mixturewas stirred at room temperature for 2 hours and the resultant solutionwas concentrated under reduced pressure. Water and ethyl acetate wereadded. The organic layer was separated and the water phase was extractedwith ethyl acetate (20 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to give the title compound (250 mg,59.5% yield).

Intermediate 197.5: (S)-Methyl2-isopropoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate

To a solution consisting of (S)-methyl2-hydroxy-5-(N-(tetrahydrofuran-3-yl) sulfamoyl) benzoate (250 mg, 0.830mmol), K₂CO₃ (344 mg, 2.49 mmol) and DMF (4 mL) was added 2-iodopropane(169 mg, 0.996 mmol). The mixture was stirred at 50° C. for 12 hours.Water (20 mL) was added into the mixture. The aqueous layer wasextracted with ethyl acetate (40 mL×2). The combined organic layers werewashed with brine (20 mL×2) and dried over Na₂SO₄. The organic layer wasfiltered and concentrated under reduced pressure to give the titlecompound (200 mg, 70.1% yield).

Compound 197:(S)—N-(5-fluoro-6-methylpyridin-2-yl)-2-isopropoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

To a solution consisting of (S)-methyl2-isopropoxy-5-(N-(tetrahydrofuran-3-yl) sulfamoyl) benzoate (200 mg,0.582 mmol)), 5-fluoro-6-methylpyridin-2-amine (87.8 mg, 0.696 mmol) andTHF (4 mL) was added LiHMDS (2.91 mL, 2.91 mmol). The mixture wasstirred at room temperature for 1 hour. The mixture was quenched withsaturated ammonium chloride. The organic layer was separated, dried overNa₂SO₄ and filtered. The filtrate was concentrated under reducedpressure. The residue was purified by prep.HPLC (Column: PhenomenexGemini 150*25 mm*5 um, Flow rate: 25 ml/min, Mobile Phase A: Base water(containing 0.05% NH₃.H₂O), Mobile Phase B: Acetonitrile.) to give thetitle compound (17.20 mg, 6.70% yield).

LC-MS (ESI): R_(T)=5.38 min, mass calcd. for C₂₀H₂₄FN₃O₅S 437.14, m/zfound 438.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (br.s, 1H), 8.33(s, 1H), 8.11 (d, J=6.4 Hz, 1H), 7.90-7.99 (m, 2H), 7.72 (t, J=9.2 Hz,1H), 7.47 (d, J=8.8 Hz, 1H), 4.97-5.04 (m, 1a), 3.66-3.73 (m, 2H),3.56-3.64 (m, 2H), 2.41 (s, 3H), 1.85-1.95 (m, 1H), 1.58-1.67 (m, 1H),1.45 (d, J=6.0 Hz, 6H).

Compound 198

Intermediate 198.2: Methyl 2-ethoxybenzoate

To a solution consisting of methyl 2-hydroxybenzoate (2.00 g, 13.1mmol), K₂CO₃ (5.45 g, 39.4 mmol) and DMF (20 mL) was added iodoethane(4.10 g, 26.3 mmol). The mixture was stirred at room temperature for 12hours. Water (20 mL) was added into the mixture. The aqueous layer wasextracted with ethyl acetate (40 mL×2). The combined organic layers werewashed with brine (20 mL×2) and dried over Na₂SO₄. The organic layer wasfiltered and concentrated under reduced pressure to give the titlecompound (2.00 g, 84.4% yield).

Intermediate 198.3: Methyl 5-(chlorosulfonyl)-2-ethoxybenzoate

To a solution consisting of methyl 2-ethoxybenzoate (1.00 g, 5.55 mmol)and sulfurous dichloride (8 mL) was added sulfurochloridic acid (0.913mL, 13.9 mmol) at 0° C. The mixture was stirred at room temperature for12 hours. The reaction mixture was poured into ice water. Title compoundwas precipitated and filtered (500 mg, 32.3% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 7.87 (d, J=1.6 Hz, 1H), 7.71-7.68 (m, 1H), 7.08 (d, J=8.8 Hz,1H), 4.08 (q, J=6.8 Hz, 2H), 3.77 (s, 3H), 1.30 (t, J=7.2 Hz, 3H).

Intermediate 198.4: (S)-methyl2-ethoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate

To a solution consisting of (S)-3-aminotetrahydrofuran hydrochloride(155 mg, 1.26 mmol, Shanghai Nuohey Chemical Technology CO., LTD.), TEA(0.527 mL, 3.78 mmol) and DCM (5 mL) was added methyl5-(chlorosulfonyl)-2-ethoxybenzoate (350 mg, 1.26 mmol). The mixture wasstirred at room temperature for 2 hours and the resultant solution wasconcentrated under reduced pressure. Water and ethyl acetate were added.The organic layer was separated and the water phase was extracted withethyl acetate (20 mL×2). The combined organic layers were washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure to give the title compound (300 mg, 72.5% yield).

Compound 198:(S)-2-ethoxy-N-(5-fluoro-6-methylpyridin-2-yl)-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

To a solution consisting of(S)-methyl2-ethoxy-5-(N-(tetrahydrofuran-3-yl) sulfamoyl) benzoate (300 mg, 0.911mmol)), 5-fluoro-6-methylpyridin-2-amine (138 mg, 1.09 mmol) and THF (4mL) was added LiHMDS (4.56 mL, 4.56 mmol). The mixture was stirred atroom temperature for 12 hours. The mixture was quenched with saturatedammonium chloride. The organic layer was separated, dried over Na₂SO₄and filtered. The filtered was concentrated under reduced pressure. Theresidue was purified by prep. HPLC (Column: Xtimate C18 150*25 mm*5 um,Flow rate: 25 ml/min, Mobile Phase A: Base water (containing 0.05%NH₃.H₂O), Mobile Phase B: Acetonitrile.) to give the title compound(138.30 mg, 35.89% yield).

LC-MS (ESI): R_(T)=5.11 min, mass calcd. for C₁₉H₂₂FN₃O₅S 423.13, m/zfound 424.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (br.s, 1H), 8.25(d, J=1.6 Hz, 1H), 8.11 (d, J=6.4 Hz, 1H), 7.91-7.97 (m, 2H), 7.72 (t,J=9.2 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 4.34 (q, J=6.8 Hz, 2H), 3.66-3.73(m, 2H), 3.55-3.64 (m, 2H), 3.34-3.37 (m, 1H), 2.40 (d, J=2.4 Hz, 3H),1.85-1.95 (m, 1H), 1.57-1.67 (m, 1H) 1.48 (t, J=6.8 Hz, 3H).

Compound 199

Intermediate 199.2: Methyl 2-propoxybenzoate

To a solution consisting of methyl 2-hydroxybenzoate (2.00 g, 13.1mmol), K₂CO₃ (5.45 g, 39.4 mmol) and DMF (20 mL) was added 1-iodopropane(4.47 g, 26.3 mmol). The mixture was stirred at room temperature for 12hours. Water (20 mL) was added into the mixture. The aqueous layer wasextracted with ethyl acetate (40 mL×2). The combined organic layers werewashed with brine (20 mL×2) and dried over Na₂SO₄. The organic layer wasfiltered and concentrated under reduced pressure to give the titlecompound (2.00 g, 78.33% yield).

Intermediate 199.3: Methyl 5-(chlorosulfonyl)-2-propoxybenzoate

To a solution consisting of methyl 2-propoxybenzoate (1.00 g, 5.15 mmol)and sulfurous dichloride (8 mL) was added sulfurochloridic acid (0.847mL, 12.9 mmol) at 0° C. The mixture was stirred at room temperature for12 hours. The reaction mixture was poured into ice water. The aqueouslayer was extracted with ethyl acetate (20 mL×2). The combined organiclayers were washed with brine (15 mL×2) and dried over Na₂SO₄. Theorganic layer was filtered and concentrated under reduced pressure. Thecrude product was purified by silica gel chromatography (eluent:petroleum ether:ethyl acetate=10:1) to give the title compound (350 mg,23.2% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (d, J=2.0 Hz, 1H), 7.71 (dd, J=1.6, 8.4Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 4.01 (t, J=6.4 Hz, 2H), 3.79 (s, 3H),1.75-1.70 (m, 2H), 0.99 (t, J=7.6 Hz, 3H).

Intermediate 199.4: (S)-methyl2-propoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzoate

To a solution consisting of (S)-3-aminotetrahydrofuran hydrochloride(148 mg, 1.20 mmol, Shanghai Nuohey Chemical Technology CO., LTD.), TEA(0.500 mL, 3.59 mmol) and DCM (5 mL) was added methyl5-(chlorosulfonyl)-2-propoxybenzoate (350 mg, 1.20 mmol). The mixturewas stirred at room temperature for 2 hours and the resultant solutionwas concentrated under reduced pressure. Water and ethyl acetate wereadded. The organic layer was separated and the water phase was extractedwith ethyl acetate (20 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to give the title compound (300 mg,73.1% yield).

Compound 199:(S)—N-(5-fluoro-6-methylpyridin-2-yl)-2-propoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl) benzamide

To a solution consisting of (S)-methyl2-propoxy-5-(N-(tetrahydrofuran-3-yl) sulfamoyl) benzoate (300 mg, 0.874mmol)), 5-fluoro-6-methylpyridin-2-amine (132 mg, 1.05 mmol) and THF (3mL) was added LiHMDS (4.37 mL, 4.37 mmol). The mixture was stirred atroom temperature for 12 hours. The mixture was quenched with saturatedammonium chloride. The organic layer was separated, dried over Na₂SO₄and filtered. The filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography to give the titlecompound (187.80 mg, 47.60% yield).

LC-MS (ESI): R₁=5.48 min, mass calcd. for C₂₀H₂₄FN₃O₅S 437.14, m/z found438.1 [M+H]⁺. Total run time was 9.5 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 10.67 (br.s, 1H), 8.28 (s, 1H), 8.11 (d, J=6.4 Hz, 1H), 7.91-7.98 (m,2H), 7.72 (t, J=9.2 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 4.25 (t, J=6.0 Hz,2H), 3.66-3.73 (m, 2H), 3.56-3.64 (m, 2H), 2.40 (d, J=1.2 Hz, 3H),1.85-1.94 (m, 3H), 1.58-1.66 (m, 1H) 1.10 (t, J=7.2 Hz, 3H).

Compound 200

Intermediate 200.2: 5-(Chlorosulfonyl)-3-fluoro-2-methoxybenzoic acid

Sulfurochloridic acid (0.484 mL, 7.35 mmol) was added into a solutionconsisting of 3-fluoro-2-methoxybenzoic acid (500 mg, 2.94 mmol) andsulfurous dichloride (5 mL) at 0° C. The mixture was stirred at roomtemperature for 2 hours. The mixture was poured into ice water. Theaqueous layer was extracted with ethyl acetate (50 mL×2). The combinedorganic layers were washed with brine and dried over Na₂SO₄. The organiclayer was filtered and concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography (eluent: petroleumether: ethyl acetate=10:1) to give title compound (200 mg, 23% yield).¹H NMR (400 MHz, DMSO-d₆) δ 7.67 (s, 1H), 7.48 (d, J=10.8 Hz, 2H), 3.82(s, 3H).

Intermediate 200.3: 5-(Chlorosulfonyl)-3-fluoro-2-methoxybenzoylchloride

Oxalyl dichloride (0.315 mL, 3.72 mmol) was added into a solutionconsisting of 5-(chlorosulfonyl)-3-fluoro-2-methoxybenzoic acid (200 mg,0.744 mmol) and DCM (4 mL) at 0° C. The reaction was stirred at roomtemperature for 1 hour. The mixture reaction was concentrated underreduced pressure to give the crude product (200 mg, 75% yield).

Intermediate 200.4:3-Fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-4-methoxybenzene-1-sulfonylchloride

4-Fluoro-3-methylaniline (87.2 mg, 0.697 mmol) was added into a solutionconsisting of 5-(chlorosulfonyl)-3-fluoro-2-methoxybenzoyl chloride (200mg, 0.697 mmol) and toluene (5 mL). The reaction was refluxed for 1hour. The mixture reaction was concentrated under reduced pressure togive the crude product (250 mg, 76% yield).

Compound 200:(S)-3-fluoro-N-(4-fluoro-3-methylphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

3-Fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-4-methoxybenzene-1-sulfonyl chloride (250 mg, 0.665 mmol) wasadded into a solution consisting of (S)-3-aminotetrahydrofuranhydrochloride (82.2 mg, 0.665 mmol, Shanghai Nuohey Chemical TechnologyCO., LTD.), TEA (0.278 mL, 2.00 mmol) and DCM (5 mL). The reaction wasstirred at room temperature for 2 hours. The mixture reaction wasconcentrated under reduced pressure. The residue was purified byprep.HPLC: (Column: Phenomenex Gemini C18 200×25 mm×10 μm, Flow rate: 25mL/min, Mobile Phase A: Base water (containing 0.05% NH₃.H₂O), MobilePhase B: Acetonitrile.). The desired fraction was collected andevaporated to remove off CH₃CN in vacuum. The residue was lyophilized todryness to give the title compound (102.90 mg, 36% yield, purity99.99%).

LC-MS (ESI): R_(T)=4.68 min, mass calcd. for C₁₉H₂₀F₂N₂O₅S 426.43, m/zfound 427.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (br.s, 1H), 8.08(s, 1H), 7.83 (dd, J=11.2 Hz, J=2.0 Hz, 1H), 7.76 (s, 1H), 7.63 (dd,J=7.2 Hz, J=2.0 Hz, 1H), 7.47-7.55 (m, 1H), 7.14 (t, J=9.6 Hz, 1H), 4.02(d, J=2.0 Hz, 3H), 3.57-3.80 (m, 4H), 3.37-3.42 (m, 1H), 2.25 (s, 3H),1.90-2.01 (m, 1H), 1.60-1.70 (m, 1H).

Compound 201

Intermediate 201.2: 5-(Chlorosulfonyl)-4-fluoro-2-methoxybenzoic acid

Sulfurochloridic acid (0.894 mL, 13.6 mmol) was added into a solutionconsisting of 4-fluoro-2-methoxybenzoic acid (1.00 g, 5.43 mmol) andsulfurous dichloride (4 mL) at 0° C. The mixture was stirred at roomtemperature for 4 hours. The mixture was stirred at 80° C. for 4 hours.The mixture was poured into ice water. The aqueous layer was extractedwith ethyl acetate (80 mL×2). The combined organic layers were washedwith brine and dried over Na₂SO₄. The organic layer was filtered andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (eluent: petroleum ether:ethyl acetate=1:1) togive the title compound (600 mg, 37% yield). ¹H NMR (400 MHz, DMSO-d₆) δ8.00 (d, J=8.8 Hz, 1H), 6.93 (d, J=12.4 Hz, 2H), 3.78 (s, 3H).

Intermediate 201.3: 5-(Chlorosulfonyl)-4-fluoro-2-methoxybenzoylchloride

Oxalyl dichloride (0.473 mL, 5.59 mmol) was added into a solutionconsisting of 5-(chlorosulfonyl)-4-fluoro-2-methoxybenzoic acid (300 mg,1.12 mmol) and DCM (4 mL) at 0° C. The reaction was stirred at roomtemperature for 1 hour. The mixture reaction was concentrated underreduced pressure to give the crude product (320 mg, 90% yield).

Intermediate 201.4:4-Fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-4-methoxybenzene-1-sulfonylchloride

4-Fluoro-3-methylaniline (126 mg, 1.00 mmol) was added into a solutionconsisting of 5-(chlorosulfonyl)-4-fluoro-2-methoxybenzoyl chloride (320mg, 1.12 mmol) and toluene (5 mL). The reaction was refluxed for 1 hour.The mixture reaction was concentrated under reduced pressure to give thecrude product (419 mg, 80% yield).

Compound 201:(S)-4-fluoro-N-(4-fluoro-3-methylphenyl)-2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)benzamide

4-Fluoro-5-((4-fluoro-3-methylphenyl)carbamoyl)-4-methoxybenzene-1-sulfonyl chloride (400 mg, 1.06 mmol) wasadded into a solution consisting of (S)-3-aminotetrahydrofuranhydrochloride (131 mg, 1.06 mmol, Shanghai Nuohey Chemical TechnologyCO., LTD.), TEA (0.445 mL, 3.19 mmol) and DCM (5 mL). The reaction wasstirred at room temperature for 2 hours. The mixture reaction wasconcentrated under reduced pressure. The residue was purified by highperformance liquid chromatography. HPLC condition: (Column: PhenomenexGemini C18 200×25 mm×10 μm, Flow rate: 25 mL/min, Mobile Phase A: Basewater (containing 0.05% NH₃.H₂O), Mobile Phase B: Acetonitrile.). Thedesired fraction was collected and evaporated to remove off CH₃CN invacuum. The residue was lyophilized to dryness to give the titlecompound (33.80 mg, 7.33% yield, purity 99.01%).

LC-MS (ESI): R_(T)=4.60 min, mass calcd. for C₁₉H₂₀F₂N₂O₅S 426.43, m/zfound 427.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (br.s, 1H), 8.22(s, 1H), 7.85 (t, J=8.8 Hz, 1H), 7.61 (dd, J=6.8 Hz, J=2.4 Hz, 1H),7.45-7.50 (m, 1H), 7.10-7.17 (m, 2H), 3.91 (s, 3H), 3.58-3.77 (m, 4H),3.40-3.41 (m, 1H), 2.24 (s, 3H), 1.93-2.00 (m, 1H), 1.68-1.75 (m, 1H).

Compound 202a-202b

Intermediate 202.2:N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-nitrobenzamide

2-Methoxy-5-nitrobenzoic acid (2.0 g, 10 mmol) was dissolved in dry DMF(20 mL). 4-Fluoro-3-methylaniline (1.9 g, 15 mmol), HATU (5.7 g, 15mmol) and DIEA (3.9 g, 30 mmol) were added to the above mixture. Themixture was stirred at 25° C. for 3 h. The mixture was poured into water(100 mL) and extracted with DCM (100 mL×3). The combined organicextracts were washed with saturated aq. NaHCO₃ (50 mL), brine (50 mL),dried over Na₂SO₄ and filtered. The filtrate was concentrated underreduced pressure to give a residue which was purified by columnchromatography over silica gel (petroleum ether:ethyl acetate=5:1) toafford the title compound (3 g, 97.2% yield).

Intermediate 202.3:5-Amino-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide

N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-nitrobenzamide (2.8 g, 9.2 mmol)was dissolved in dry MeOH (50 mL). Pd/C (280 mg, 10%) was added to theabove mixture. The mixture was stirred at 25° C. under H₂ (50 psi) for 5h. The reaction mixture was filtered and the filtrate was concentratedunder reduced pressure to afford the title compound (2.5 g, 99% yield).

Compound 202a(S*)N-4-fluoro-3-methylphenyl)-2-methoxy-5-(tetrahydrofuran-3-sulfonamido)benzamideCompound 202b(R*)N-4-fluoro-3-methylphenyl)-2-methoxy-5-(tetrahydrofuran-3-sulfonamido)benzamide

To a solution consisting of5-amino-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide (300 mg, 1.09mmol), DBU (500 mg, 3.28 mmol) and THF (6 mL) were addedtetrahydrofuran-3-sulfonyl chloride (373 mg, 2.19 mmol). The reactionmixture was refluxed for 12 hours. Water (10 mL) was added into themixture. The resultant mixture was extracted with ethyl acetate (20mL×2). The combined organic extracts were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated under reducedpressure. The residue was purified by prep. HPLC (Column: OJ (250×30 mm5 μm), Flow rate: 25 ml/min, Mobile Phase A: 40% MeOH+NH₃H₂O 50 mL/min220 nm water, Mobile Phase B: Acetonitrile) to give the crude compoundwhich was further purified by prep.SFC (separation condition: Column:ChiralPak OJ-H, Daicel Chemical Industries, Ltd, 250*30 mm I.D., 5 μm;Mobile phase: A: Supercritical CO₂, B: Methanol (0.1% NH₃.H₂O),A:B=65:35 at 60 mL/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar;Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.;Wavelength: 220 nm) to afford Compound 202a (58.5 mg, 13.08% yield,purity 100%) and Compound 202b (55.8 mg, 12.53% yield, purity 100%).Compound 202a:

LC-MS (ESI): R_(T)=4.65 min, mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/zfound 409.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (br.s, 1H), 7.63(dd, J=6.8 Hz, J=2.4 Hz 1H), 7.52-7.58 (m, 1H), 7.49 (d, J=2.8 Hz, 1H),7.35 (dd, J=8.8 Hz, J=2.8 Hz 1H), 7.07-7.20 (m, 2H), 3.91-3.97 (m, 1H),3.88 (s, 3H), 3.77-3.85 (m, 3H), 3.60-3.67 (m, 1H), 2.23 (d, J=1.6 Hz,3H), 2.10-2.16 (m, 2H). Compound 202b: LC-MS (ESI): R_(T)=4.65 min, masscalcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found 409.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 10.10 (br.s, 1H), 7.63 (dd, J=6.8 Hz, J=2.4 Hz 1H), 7.52-7.58(m, 1H), 7.49 (d, J=2.8 Hz, 1H), 7.35 (dd, J=8.8 Hz, J=2.8 Hz 1H),7.07-7.20 (m, 2H), 3.91-3.97 (m, 1H), 3.88 (s, 3H), 3.76-3.85 (m, 3H),3.60-3.67 (m, 1H), 2.23 (d, J=1.6 Hz, 3H), 2.10-2.16 (m, 2H).

Compound 203

Intermediate 203.2: 4-Methoxy-3-nitrobenzene-1-sulfonyl chloride

1-Methoxy-2-nitrobenzene (3.00 g, 19.6 mmol) was dissolved insulfurochloridic acid (30.0 g, 257 mmol) at 0° C. and then stirred atroom temperature for 1 h. The mixture was poured into ice water. Thetitle compound was precipitated and filtered. (4.15 g, 75.76% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 7.94 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.29 (d,J=8.4 Hz, 1H), 3.89 (s, 3H).

Intermediate 203.3:(S)-4-Methoxy-3-nitro-N-(tetrahydrofuran-3-yl)benzenesulfonamide

To a solution consisting of (S)-3-aminotetrahydrofuran hydrochloride(589 mg, 4.77 mmol), TEA (1.66 mL, 11.9 mmol) and DCM (10 mL) was added4-methoxy-3-nitrobenzene-1-sulfonyl chloride (1.00 g, 3.97 mmol) at 0°C. The mixture was stirred at room temperature for 4 h. The resultantsolution was concentrated under reduced pressure to give the titlecompound (1.00 g, 67% yield).

Intermediate 203.4: (S)-3-Amino-4-methoxy-N-(tetrahydrofuran-3-yl)benzenesulfonamide

To a solution consisting of(S)-4-Methoxy-3-nitro-N-(tetrahydrofuran-3-yl)benzenesulfonamide (1 g,3.31 mmol) and methanol (30 mL) was added Pd(OH)₂/C (20% w/w, 100 mg).The mixture was hydrogenated at room temperature (30 psi) for 2 hrs. Thecatalyst was filtered off and the filtrate was concentrated to drynessto give the title compound (800 mg, 67% yield).

Compound 203:(S)-4-Fluoro-N-(2-methoxy-5-(N-(tetrahydrofuran-3-yl)sulfamoyl)phenyl)-3-methylbenzamide

To a solution consisting of 4-fluoro-3-methylbenzoic acid (226 mg, 1.47mmol), (S)-3-amino-4-methoxy-N-(tetrahydrofuran-3-yl)benzenesulfonamide(400 mg, 1.47 mmol), TEA (0.614 mL, 4.41 mmol) and DMF (5 mL) was addedHATU (670 mg, 1.76 mmol). The reaction mixture was stirred at roomtemperature for 12 hrs. Water was added into the mixture. The aqueouslayer was extracted with ethyl acetate (25 mL×2). The organic layerswere combined, washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated to dryness under reduced pressure. The residuewas purified by prep.HPLC (Column: YMC-Actus.Triart C18 150×30×5 um,Flow rate: 30 mL/min, Mobile Phase A: Base water (containing 0.05%NH₃.H₂O), Mobile Phase B: Acetonitrile, Gradient: 25-55% (% B)) to givethe title compound (191.00 mg, purity 99.99%, 31.86% yield). LC-MS(ESI): R_(T)=4.63 min, mass calcd. for C₁₉H₂₁FN₂O₅S 408.12, m/z found409.1 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (br.s, 1H), 8.25 (d,J=2.5 Hz, 1H), 7.94 (dd, J=1.9, 7.4 Hz, 1H), 7.89-7.83 (m, 1H), 7.65(dd, J=2.3, 8.8 Hz, 1H), 7.33-7.28 (m, 2H), 3.93 (s, 3H) 3.73-3.54 (m,4H), 3.38-3.36 (m, 1H), 2.32 (d, J=1.8 Hz, 3H), 1.97-1.86 (m, 1H),1.69-1.58 (m, 1H).

Compound 204a-204b

Intermediate 204.2:N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(tetrahydrofuran-3-sulfonamido)benzamide

5-Amino-N-(4-fluoro-3-methylphenyl)-2-methoxybenzamide (300 mg, 1.094mmol) and DBU (426 mg, 2.798 mmol) were dissolved in THF (10 mL)followed by the addition of tetrahydrofuran-3-sulfonyl chloride (313 mg,1.835 mmol). The mixture was stirred at 90° C. for 16 hours beforeconcentrating it to dryness. The residue was purified by prep.TLC(petroleum ether:ethyl acetate=3:1) and prep.HPLC (formic acid asadditive) to give the title compound (80 mg, 17.92% yield).

Compound 204a:(R*)—N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-methyltetrahydrofuran-3-sulfonamido)benzamideCompound 204b:(S*)—N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(N-methyltetrahydrofuran-3-sulfonamido)benzamide

N-(4-Fluoro-3-methylphenyl)-2-methoxy-5-(tetrahydrofuran-3-sulfonamido)benzamide(80 mg, 0.196 mmol) and K₂CO₃ (59 mg, 0.427 mmol) were dissolved in DMF(3 mL) followed by the addition of iodomethane (34 mg, 0.24 mmol). Themixture was stirred at 90° C. for 16 hours before concentrating it todryness. The residue was purified by prep.TLC (petroleum ether:ethylacetate=3:1), prep-HPLC (RP-18 (NH₄HCO₃ as additive) and SFC to obtainthe title two compounds. Compound 204a (9.11 mg, 11.22% yield).

LC-MS (ESI): mass calcd. for C₂₀H₂₃FN₂O₅S 422.13, m/z found 423.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) 10.14 (br.s, 1H), 7.69-7.60 (m, 2H),7.59-7.50 (m, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H),4.18-4.08 (m, 1H), 3.95-3.91 (m, 1H), 3.90 (s, 3H), 3.79-3.72 (m, 2H),3.66-3.59 (m, 1H), 3.27 (s, 3H), 2.23 (s, 3H), 2.21-2.15 (m, 1H),2.04-1.95 (m, 1H). Compound 204b (24.60 mg, 29.59% yield). LC-MS (ESI):mass calcd. for C₂₀H₂₃FN₂O₅S 422.13, m/z found 423.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) 10.14 (br.s, 1H), 7.69-7.60 (m, 2H), 7.59-7.50 (m, 2H),7.20 (d, J=8.0 Hz, 1H), 7.11 (t, J=8.0 Hz, 1H), 4.18-4.08 (m, 1H),3.95-3.91 (m, 1H), 3.90 (s, 3H), 3.79-3.72 (m, 2H), 3.66-3.59 (m, 1H),3.27 (s, 3H), 2.23 (s, 3H), 2.21-2.15 (m, 1H), 2.04-1.95 (m, 1H).

Biological Examples—5HTR2b Antagonist Activity of Compounds

The 5HTR2B antagonist activity was measured using human Maverick/293cells in a calcium mobilization assay. The measurement starting withplating human Maverick/293 cells (log phase) onto 96-well black andincubate at 37° C. overnight, Followed by starving cells for 2 h bychanging complete medium to DMEM without FBS, removing the medium fromthe 96-well plate. Loading staining calcium buffer into each well andincubated the plate at 37° C. for 50 min. After removal of stainingcalcium buffer, diluted antagonist were added into the well, incubate 15to 30 minutes. Dispense serotonin as the 5HTR2B agonists into each well.Intracellular calcium concentration is recorded for 80 seconds bymonitoring an emission at a wavelength of 525 nm with an excitationwavelength of 485 nm. Inhibition efficiency of the cell line wasdetermined following the equation: % Inhibition=100%−(D−B)/(S−B)*100%.(S: The peak value in the presence of agonist serotonin; D: The peakvalue in the presence of different dilution compound or serotonin; B:The peak value in the presence of calcium HBSS buffer only). Finally thedata was displayed graphically using GraphPad Prism 5.0. A dose responsecurve was fitted using nonlinear regression model with a sigmoidal doseresponse. The IC50 was automatically produced by GraphPad Prism 5.0.Results are displayed in Table 3.

TABLE 3 Ca assay Co. IC50 No. (nM)   1 2.3   2 0.6   3 1.7   4 0.7   54.2   6a 18   6b 1.9   7 5.4   7a 3.8   7b 6.9   8 2.5   9 2.2  10 4.5  10a 4.5   10b 12   11a 68   11b 5.1 12 9.3   12a 1.8   12b 122 13 66.314 14.6   15a 2   15b 1.0   16a 1.1   16b 9.1 17 7.2 18 222 19 173 204.4 21 1.6 22 610   23a 4.7   23b 5  24 47  25 1.4  26 1.3  27 1.1   28a19   28b 119   29a 3.0   29b 4.6  30 24  31 55   32a 1.8   32b 8.5   33a0.4   33b 0.4   34a 1.4   34b 167   35a 0.7   35b 4.3  36 2.7  37 0.8 38 0.6  39 3.6   40a 1.7   40b 9.5  41 0.7  42 2.2  43 7.2   44a 2.4  44b 3.2   45a 1.3   45b 1.9   46a 1.5   46b 1.8  47 0.5  48 2.7   49a3.4   49b 9.0  50 7.6  51 1.0   52a 50   52b 4.5  53 0.3   54a 1.1   54b1.2   55a 0.3   55b 0.1   56a 0.1   56b 0.2   57a 0.2   57b 0.2  58 0.2  59a 0.2   59b 0.2   60a 0.4   60b 0.4   61a 0.1   61b 0.2   61c 0.2 62 0.1  63 1.3  64 65  65 0.34  66 0.2  67 8.8  68 2.9  69 1.5  70 0.3 71 1.6  72 5.1  73 5.5  74 0.8  75 9.1  76 3.1  77 5.3  78 2.4  79 98 80 574  81 32  82 1.1  83 126  84 716  85 1.5  86 1.8  87 29  88 28  891947  90 1361  91 92  97 136  93 1063  94 12  95 648  96 84  97 186  9837  99 1.6 100 4.6 101 219 102 435 103 8.4 104 201 105 12 106 596 107 27108 5.5 109 231 110 10 111 1.3 112 2.9 113 17 114 0.4 115 0.8 116 5.4117 64 118 6.7 119 1.4 120 50 121 3.8 122 0.6 123 0.2 124 6.3 125 28 12612 127 0.1 128 1.2 129 12 130 2.1 131 1.3 132 163 133 405 134 0.5 1350.1 136 0.4  137a 17.1  137b 39  138a 159  138b 329  139a 11  139b 3.9 140a 3.9  140b 0.9 141 2.8  142a 2.2  142b 1.1  143a 0.7  143b 5.9 144a 0.5  144b 0.3  145a 2.5  145b 1.0  146a 0.8  146b 1.0  147a 3.4 147b 2.1 148 161 149 8.4 150 9.9 151 39 152 11 153 1.0 154 0.6 155 0.2156 159 157 53 158 0.17 159 0.7 160 4.6 161 79 162 0.5 163 0.9 164 1.1165 511 166 0.16 167 0.32 168 3.9 169 65 170 58 171 106 172 33 173 0.8 174a 3.9  174b 1.7 175 1.6 176 5.0 177 4.2 178 0.3 179 0.1 180 3.3 1814.5 182 0.3 183 0.5 184 0.3 185 0.8 186 0.3 187 0.7 188 1.6 189 14 1900.9 191 1.1 192 0.4 193 3.2 194 1.1 195 0.9 196 19 197 5.3 198 0.7 1993.7 200 3.3 201 8.6  202a 1.0  202b 2.8 203 13  204a 50  204b 56

The invention claimed is:
 1. A compound of Formula (I)

or a stereoisomer or tautomeric form thereof, wherein: Ar represents amonocyclic or bicyclic aromatic ring, optionally containing one or moreheteroatoms each independently selected from the group consisting of O,S and N, such aromatic ring optionally being substituted with one ormore substituents each independently selected from the group consistingof halogen, —CN, —OR⁶, C₁-C₃ alkyl, C₃-C₇cycloalkyl, CHF₂, CH₂F and CF₃;R¹ represents a 3-7 membered saturated ring optionally containing one ormore heteroatoms each independently selected from the group consistingof O, S and N, such 3-7 membered saturated ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of Fluor, —OH, oxo and C₁-C₃ alkyl optionallysubstituted with one or more Fluor and/or OH; R⁶ represents hydrogen,C₁-C₃ alkyl optionally substituted with one or more Fluor, or —C₁-C₃alkyl-O(R⁵); R⁵ represents hydrogen or C₁-C₃ alkyl; or apharmaceutically acceptable salt or a solvate thereof.
 2. The compoundaccording to claim 1, wherein Ar is phenyl, pyridine or benzimidazoleoptionally substituted with one or more substituents each independentlyselected from the group consisting of —CN, halogen, C₁-C₃ alkyl,C₁-C₃cycloalkyl, CHF₂, CH₂F and CF₃.
 3. The compound according to claim1 wherein R¹ represents a 4-7 membered saturated ring containing carbonatoms and optionally one oxygen atom, such 4-7 membered saturated ringoptionally substituted with one or more of C₁-C₃alkyl and/or OH.
 4. Thecompound according to claim 1, wherein R¹ represents a 5 memberedsaturated ring containing carbon atoms and one oxygen atom.
 5. Acompound according to claim 1, wherein Ar is phenyl or pyridine,optionally substituted with one or more substituents each independentlyselected from halogen, —OH, C₁-C₃ alkyl, C₁-C₃cycloalkyl, CHF₂, CH₂F andCF₃.
 6. A method of preventing or treating liver fibrosis and/orcirrhosis in a mammal comprising administering a therapeuticallyeffective amount of at least one compound according to Formula A

or a stereoisomer or tautomeric form, and/or a salt or solvate thereof,wherein Ar represents a monocyclic or bicyclic aromatic ring, optionallycontaining one or more heteroatoms each independently selected from thegroup consisting of O, S and N, such aromatic ring optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of hydrogen, halogen, —CN, —OH, C₁-C₃ alkyl,C₃-C₇cycloalkyl, —O(R⁶), CHF₂, CH₂F and CF₃; R¹ represents hydrogen, a3-7 membered saturated ring optionally containing one or moreheteroatoms each independently selected from the group consisting of O,S and N, or C₁-C₆ alkyl, such 3-7 membered saturated ring or C₁-C₆alkyloptionally being substituted with one or more substituents eachindependently selected from the group consisting of C₁-C₃ alkyl,halogen, CHF₂, CH₂F and CF₃, —CN, —C(═O)R⁵, oxo-C(═O) N(R⁶)₂, —N(R⁶)₂and —OR⁶; R² represents hydrogen, or C₁-C₃ alkyl; R³ represents Fluor or—OC₁-C₃ alkyl optionally substituted with one or more Fluor; R⁴represents hydrogen, Fluor or —OC₁-C₃ alkyl; R⁶ represents hydrogen,C₁-C₃ alkyl optionally substituted with one or more Fluor, or —C₁-C₃alkyl-O(R⁵); R⁵ represents hydrogen or C₁-C₃ alkyl.
 7. The methodaccording to claim 6, wherein R³ represents Fluor or —OC₁-C₃ alkyl andR² and R⁴ represent hydrogen.
 8. The method according to claim 6,wherein Ar is phenyl, pyridine or benzimidazole optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, C₁-C₃ alkyl, C₁-C₃cycloalkyl, CHF₂, CH₂F and CF₃.9. The method according to claim 6, wherein R¹ represents a 5 memberedsaturated ring containing carbon atoms and one oxygen atom.
 10. Themethod according to claim 6, wherein Ar is phenyl optionally substitutedwith one or more substituents each independently selected from —CN,C₁-C₃ alkyl, C₁-C₃cycloalkyl, CHF₂, CH₂F and CF₃.
 11. A pharmaceuticalcomposition comprising a compound according to claim 1, and apharmaceutically acceptable carrier.
 12. A product containing (a) acompound of formula (I) as defined in claim 1, and (b) another liverfibrosis and/or cirrhosis inhibitor, as a combined preparation forsimultaneous, separate or sequential use in the treatment of liverfibrosis and/or cirrhosis.